Process for the preparation of substituted cycloserines

ABSTRACT

The present invention relates to processes for the preparation of substituted cycloserine compounds of formula (I) wherein R 1  is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 6 cycloalkyl, aryl or aryl substituted by one to five R 11 , or aryl-C 1 -C 4 alkylene or aryl-C 1 -C 4 alkylene substituted by one to five R 11 ; and each R 11  is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano or halogen; The invention also relates to intermediates produced by the processes. Compounds of formula (I) are useful intermediates for the production of compounds in the agricultural and pharmaceutical fields.

The present invention relates to novel methods of producing2-substituted cycloserines (4-amino-isoxazolidin-3-one) andintermediates useful in the preparation of 2-substituted cycloserines.

2-substituted cycloserines are useful intermediates in the preparationof certain insecticidally active compounds, for example those describedin WO2011/067272 and WO2012/163959. Some cycloserines are also used asbroad spectrum antibiotics.

2-substituted cycloserines are prepared in WO2011/067272 according tothe method described in Chem. Pharm. Bull. 2002, 50(4) 554-557, whichinvolves alkylation of the parent cycloserine or cycloserine derivativesuch as a tert-butyloxycarbonyl. Similar procedures are described inTet. Lett. 2012, 2564-2567.

The main drawbacks of the known methods of alkylating cycloserinesinclude the formation of isomeric by-products arising from O-alkylationinstead of the desired N-alkylation, and possible epimerisation of thecycloserine stereo-centre, particularly when strongly basic conditionsare employed. There are also limitations imposed by the low reactivityand accessibility of the corresponding alkylation reagents.

It has been found that the insecticides described in WO2011/067272 andWO2012/163959 are more efficacious when the cycloserine moiety ispresent in the molecule with the D stereo-configuration, making itparticularly desirable to find methods of derivatising cycloserine thatreduce epimerisation.

Although regioselective derivatisation of cycloserine has been describedin Tet. Lett. 2012, 2564-2567, special equipment was needed and thismethod is not appropriate for commercial scale production.

Methods of derivatising cycloserines have now surprisingly been foundthat allow preparation of 2-substituted cycloserines without requiringcycloserine starting material. These methods also provide furtheradvantages by avoiding the need for protecting groups and allowingpreparation of 2-substituted cycloserines with a defined stereoconfiguration.

In an aspect the invention provides a process for the preparation of acompound of formula (I)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;comprisinga. reacting a compound of formula (II) or a salt thereof

wherein R¹ is as defined for the compound of formula (I)with a compound of formula (III)

wherein R² is a leaving group, for example halogen,C₁-C₈alkylsulfonyloxy, C₁-C₈haloalkylsulfonyloxy, C₁-C₈arylsulfonyloxyor C₁-C₈arylsulfonyloxy substituted by one to five R¹¹, or a phosphonateester; and each R¹¹ is as defined for the compound of formula (I) in thepresence of a base.

Examples of suitable and preferred bases for performing the step a. aregiven below.

In an aspect the invention provides a process for the preparation of acompound of formula (I)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;comprisinga-1. reacting the compound of formula (II) with the compound of formula(III) to produce the compound of formula (IV) or a salt thereof

wherein R¹ and R² are as defined for the compound of formula (I) andformula (III) in the presence of a suitable acid; anda-2. converting the compound of formula (IV) to the compound of formula(I) in the presence of a suitable base.

Examples of suitable acids used in the step a-1 and preferred acids usedin the step a-1 are given below. Examples of suitable bases used in thestep a-2 and preferred bases used in the step a-2 are given below.

In a further aspect the invention provides a process for the preparationof a compound of formula (IV) comprising performing step a-1 as definedabove. In a further aspect the invention provides a process for thepreparation of a compound of formula (I)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;comprising the step a-2a-2. converting the compound of formula (IV)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹;R² is C₁-C₈alkylsulfonyloxy, C₁-C₈haloalkylsulfonyloxy,C₁-C₈arylsulfonyloxy or C₁-C₈arylsulfonyloxy substituted by one to fiveR¹¹, or a phosphonate ester; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;to the compound of formula (I) in the presence of a suitable base.

In a further aspect the invention provides a process for the preparationof a compound of formula (I) comprising performing step a-2. as definedabove. In a further aspect the invention provides a process for thepreparation of a compound of formula (IV)

wherein R¹ and R² are as defined for the compound of formula (I) andformula (III)comprising reacting according to the step a-1. the compound of formula(II) with the compound of formula (III) to produce the compound offormula (IV)

In one aspect the present invention relates to a process for thepreparation of a compound of formula (I)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;comprisingreacting a compound of formula (II) or a salt thereof

wherein R¹ is as defined for the compound of formula (I);with a compound of formula (III)

in the presence of a basewhereinR² is a leaving group selected from halogen, C₁-C₈alkylsulfonyloxy,C₁-C₈haloalkylsulfonyloxy, C₁-C₈arylsulfonyloxy or C₁-C₈arylsulfonyloxysubstituted by one to five R¹¹, or a phosphonate ester; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen.

In one aspect the present invention relates to a process for thepreparation of a compound of formula (I)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;comprisinga-1. reacting the compound of formula (II)

with the compound of formula (III)

in the presence of a suitable acidwhereinR² is a leaving group selected from halogen, C₁-C₈alkylsulfonyloxy,C₁-C₈haloalkylsulfonyloxy, C₁-C₈arylsulfonyloxy or C₁-C₈arylsulfonyloxysubstituted by one to five R¹¹, or a phosphonate ester; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;to produce the compound of formula (IV) or a salt thereof

wherein R¹ and R² are as defined for the compound of formula (I) andformula (III)anda-2. converting the compound of formula (IV) to the compound of formula(I) in the presence of a suitable base.

In one aspect the present invention relates to a process for thepreparation of a compound of formula (IV)

comprisinga-1. reacting the compound of formula (II)

with the compound of formula (III)

in the presence of a suitable acidwhereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹;R² is a leaving group selected from halogen, C₁-C₈alkylsulfonyloxy,C₁-C₈haloalkylsulfonyloxy, C₁-C₈arylsulfonyloxy or C₁-C₈arylsulfonyloxysubstituted by one to five R¹¹, or a phosphonate ester;each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen.

In one aspect the present invention relates to a process for thepreparation of a compound of formula (I)

comprising the step a-2a-2. converting the compound of formula (IV)

to the compound of formula (I) in the presence of a suitable basewhereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹;R² is C₁-C₈alkylsulfonyloxy, C₁-C₈haloalkylsulfonyloxy,C₁-C₈arylsulfonyloxy or C₁-C₈arylsulfonyloxy substituted by one to fiveR¹¹, or a phosphonate ester; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen.

In one aspect the present invention relates to a compound of formula(IV)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹;R² is C₁-C₈alkylsulfonyloxy, C₁-C₈haloalkylsulfonyloxy,C₁-C₈arylsulfonyloxy or C₁-C₈arylsulfonyloxy substituted by one to fiveR¹¹, or a phosphonate ester; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;or a salt or N-oxide thereof

In one aspect the present invention relates to a process for thepreparation of a compound of formula (I)

comprisingi. reacting a compound of formula (II) or a salt thereof

with a compound of formula (V)

in the presence of a suitable base to produce a compound of formula (VI)

andii. converting the compound of formula (VI) to a compound of formula (I)by treatment of the compound of formula (VI) with an aqueous basewhereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, C₃-C₆ cycloalkyl, aryl or arylsubstituted by one to five R¹¹, or aryl-C₁-C₄alkylene oraryl-C₁-C₄alkylene substituted by one to five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;R⁷ is hydroxy or halogen or OM where M is Na, K, Li.

In one aspect the present invention relates to a compound of formula (V)

wherein R⁷ is is OM where M is Na, K, Li.

A compound of formula (VI)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, C₃-C₆ cycloalkyl, aryl or arylsubstituted by one to five R¹¹, or aryl-C₁-C₄alkylene oraryl-C₁-C₄alkylene substituted by one to five R¹¹;each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;or a salt or N-oxide thereof

In one aspect the present invention relates to a compound of formula (I)

wherein R¹ is aryl or aryl substituted by one to five R¹¹;each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen

A process for the preparation of a compound of formula (V)

wherein R⁷ is OM where M is Na, K, Li.comprising the reaction of a compound (XV)

where R¹² is C₁-C₄ alkylwith an alkali metal salt MOH wherein M is Na, K, Li.

In one aspect the present invention relates to a process for thepreparation of a compound of formula (V)

wherein R⁷ is OM where M is Na, K, Li.comprising the reaction of a compound (XVI)

R¹³ is C₁-C₄ alkyl, benzyl or phenylwith an alkali metal salt MOH wherein M is Na, K, Li.

In the processes above the compounds of formula (I), (III) and (IV) arepreferably compounds of formula (I*), (III*) and (IV*) or enrichedmixtures thereof

wherein R¹ is as defined for the compound of formula (I) and R² is aleaving group, or a salt or N-oxide thereof.

In a further aspect the invention provides a compound of formula (IV)

wherein R¹ is as defined for the compound of formula (I) and R² is aleaving group as defined below, or a salt or N-oxide thereof

Preferably the compound of formula (IV) is a compound of formula (IV*).

In a further aspect the invention provides a process for the preparationof a compound of formula (I)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, C₃-C₆ cycloalkyl, aryl or arylsubstituted by one to five R¹¹, or aryl-C₁-C₄alkylene oraryl-C₁-C₄alkylene substituted by one to five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;comprisingi. reacting a compound of formula (II) or a salt thereof.

wherein R¹ is as defined for the compound of formula (I)with a compound of formula (V)

wherein R⁷ is hydroxy or halogen or OM where M is Na, K, Li.in the presence of a suitable base to produce a compound of formula (VI)

wherein R¹ as defined for the compound of formula (I); andii. converting the compound of formula (VI) to a compound of formula (I)by treatment of the compound of formula (VI) with an aqueous base.

Examples of suitable bases used in the step i and in the step ii andpreferred bases used in the step i and in the step ii. are given below.

Preferably R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted byone to five R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substitutedby one to five R¹¹; and

each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;Preferably R⁷ is hydroxy or halogen.

Equally preferred R¹ is C₃-C₆ cycloalkyl; and R⁷ is OM where M is Na, K,Li.

In a further aspect the invention provides a process for the preparationof a compound of formula (VI) as defined in above, comprising performingstep i. as defined above. In a further aspect the invention provides aprocess for the preparation of a compound of formula (I) as definedabove, comprising performing step ii. as defined above.

In the processes above the compounds of formula (I), (V) and (VI) arepreferably compounds of formula (I*), (V*) and (VI*) or enrichedmixtures thereof:

wherein R¹ is as defined for the compound of formula (I) and R⁷ is asdefined for the compound of formula (V).

In a further aspect the invention provides a compound of formula (VI)

wherein R¹ is as defined for the compound of formula (I) or a salt ofN-oxide thereof. Preferably the compound of formula (VI) is a compoundof formula (VI*).

In a further aspect the invention provides a compound of formula (V)

wherein R⁷ is OLi, ONa or OK

In a further aspect the invention provides a compound of formula (I)

wherein R¹ is aryl or aryl substituted by one to five R¹¹.each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen

All aspects of the invention may also include further processing of thecompound of formula (I). In particular, the process may include reactingthe compound of formula (I) with a second compound, wherein the secondcompound comprises a carboxylic acid, acid halide, ester or thioesterfunctional group, and the reaction comprises reacting the aminefunctional group of the compound of formula (I) with the carboxylicacid, acid halide, ester or thioester functional group of the secondcompound such that the compound of formula (I) is coupled to the secondcompound via an amide functional group, or wherein the second compoundcomprises a dicarbonate group, and the reaction comprises reacting theamine functional group of the compound of formula (I) with thedicarbonate group of the second compound, such that the compound offormula (I) is coupled to the second compound via a carbamate functionalgroup.

In one embodiment the second compound is a compound of formula (XII)

whereinX is a leaving group, cyano, formyl, acetyl, C(O)CH═C(R³)R⁴,C(O)CH₂C(OH)(R³)R⁴ or group A

—B¹—B²—B³— is —C═N—O—, —C═N—CH₂—, —C═CH—O— or —N—CH₂—CH₂—;A¹, A², A³ and A⁴ are independently of one another C—H, C—R⁵, ornitrogen;R³ is C₁-C₈haloalkyl;R⁴ is aryl or aryl substituted by one to three R⁶, or R⁴ is heterocyclylor heterocyclyl substituted by one to three R⁶;each R⁵ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₃-C₈cycloalkyl, C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl,C₂-C₈alkynyl, C₂-C₈haloalkynyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy,C₁-C₈alkoxycarbonyl-, or two R⁵ on adjacent carbon atoms together form a—CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;each R⁶ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, or C₁-C₈haloalkoxy;R⁸ is hydroxy, C₁-C₆alkoxy or chloro, fluoro, bromo, or SR^(x) whereinR^(x) is H, C₁-C₆alkyl, imidazole or pyrrole; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;and the process results in a compound of formula (VIII)

wherein A¹, A², A³, A⁴ and X are as defined for the compound of formula(XII) and R¹ is as defined for the compound of formula (I).

In another embodiment the second compound is a compound of formula(XIII)

wherein R⁹ is hydrogen, C₁-C₈alkyl or C₁-C₈haloalkyl and R⁸ is asdefined for compounds of formula (XII);and the process results in a compound of formula (IX)

wherein R¹ is as defined for the compound of formula (I) and R⁹ is asdefined for the compound of formula (XIII).

In another embodiment the second compound is a compound of formula(XIVa) or (XIVb)

wherein each R¹⁰ is independently C₁-C₈alkyl, C₁-C₈haloalkyl,aryl-C₁-C₄alkylene- or aryl-C₁-C₄alkylene-substituted by one to fiveR¹¹, wherein each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₄alkoxy, C₁-C₄haloalkoxy, cyano or halogen;and the process results in a compound of formula X

wherein R¹ is as defined for the compound of formula (I) and R¹⁰ is asdefined for the compound of formula (XIVa) and XIVb.

In a further aspect the invention provides a process wherein thecompound of formula (I) is reacted with a second compound, wherein thesecond compound comprises a carboxylic acid, acid halide, ester orthioester functional group, and the reaction comprises reacting theamine functional group of the compound of formula (I) with thecarboxylic acid, acid halide, ester or thioester functional group of thesecond compound such that the compound of formula (I) is coupled to thesecond compound via an amide functional group, or wherein the secondcompound comprises a dicarbonate group, and the reaction comprisesreacting the amine functional group of the compound of formula (I) withthe dicarbonate group of the second compound, such that the compound offormula (I) is coupled to the second compound via a carbamate functionalgroup. Preferably in the process wherein the compound of formula (I) isreacted with a second compound

whereinthe second compound is a compound of formula (XII)

and the process results in a compound of formula (VIII)

whereinX is a leaving group selected from halogen, C₁-C₈alkylsulfonyloxy,C₁-C₈haloalkylsulfonyloxy, C₁-C₈arylsulfonyloxy or C₁-C₈arylsulfonyloxysubstituted by one to five R¹¹, or a phosphonate ester, cyano, formyl,acetyl, C(O)CH═C(R³)R⁴, C(O)CH₂C(OH)(R³)R⁴ or group A

—B¹—B²—B³— is —C═N—O—, —C═N—CH₂—, —C═CH₂—O— or —N—CH₂—CH₂—;A¹, A², A³ and A⁴ are independently of one another C—H, C—R⁵, ornitrogen;R³ is C₁-C₈haloalkyl;R⁴ is aryl or aryl substituted by one to three R⁶, or R⁴ is heterocyclylor heterocyclyl substituted by one to three R⁶;each R⁵ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₃-C₈cycloalkyl, C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl,C₂-C₈alkynyl, C₂-C₈haloalkynyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy,C₁-C₈alkoxycarbonyl-, or two R⁵ on adjacent carbon atoms together form a—CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;each R⁶ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, or C₁-C₈haloalkoxy;R⁸ is hydroxy, C₁-C₆alkoxy, fluoro, chloro, bromo, or SR^(x) whereinR^(x) is H, C₁-C₆alkyl, imidazole or pyrrole; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;orthe second compound is a compound of formula (XIII)

wherein and the process results in a compound of formula (IX)

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹; andR⁹ is hydrogen, C₁-C₈alkyl or C₁-C₈haloalkyl and R⁸ is as defined forcompound of formula (XII);each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;orthe second compound is a compound of formula (XIVa) or (XIVb)

and the process results in a compound of formula X

whereinR¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹;each R¹⁰ is independently C₁-C₈alkyl, C₁-C₈haloalkyl,aryl-C₁-C₄alkylene- or aryl-C₁-C₄alkylene-substituted by one to fiveR¹¹;each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen;

In a further aspect the invention provides a process for the preparationof a compound of formula (VIII) or a salt or N-oxide thereof

comprising the preparation of a compound of formula (I)

according to the process any one of claim 1 or 2 or 3 or 4 or 6, andreacting the compound of formula (I) with compound of formula (XII)

whereinX is a leaving group selected from halogen, C₁-C₈alkylsulfonyloxy,C₁-C₈haloalkylsulfonyloxy, C₁-C₈arylsulfonyloxy or C₁-C₈arylsulfonyloxysubstituted by one to five R¹¹, or a phosphonate ester, cyano, formyl,acetyl, C(O)CH═C(R³)R⁴, C(O)CH₂C(OH)(R³)R⁴ or group A

—B¹—B²—B³— is —C═N—O—, —C═N—CH₂—, —C═CH₂—O— or —N—CH₂—CH₂—;A¹, A², A³ and A⁴ are independently of one another C—H, C—R⁵, ornitrogen;R³ is C₁-C₈haloalkyl;R⁴ is aryl or aryl substituted by one to three R⁶, or R⁴ is heterocyclylor heterocyclyl substituted by one to three R⁶;each R⁵ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₃-C₈cycloalkyl, C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl,C₂-C₈alkynyl, C₂-C₈haloalkynyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy,C₁-C₈alkoxycarbonyl-, or two R⁵ on adjacent carbon atoms together form a—CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;each R⁶ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, or C₁-C₈haloalkoxy;R⁸ is hydroxy, C₁-C₆alkoxy, chloro, cluoro, bromo, or SR^(x) whereinR^(x) is H, C₁-C₆alkyl, imidazole or pyrrole;R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹; andeach R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen.

The compounds of the invention may exist in different geometric oroptical isomers or tautomeric forms. In particular, the compounds of theinvention may contain one or more asymmetric carbon atoms and may existas enantiomers (or as pairs of diastereoisomers) or as mixtures of such.This invention covers all such isomers and tautomers and mixturesthereof in all proportions as well as isotopic forms such as deuteratedcompounds. The compounds and processes of the invention include N-oxidesand salts where possible.

Alkyl groups (either alone or as part of a larger group, such asalkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl- oralkoxycarbonyl-) can be in the form of a straight or branched chain andare, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl,2-methyl-prop-1-yl or 2-methyl-prop-2-yl. The alkyl groups arepreferably C₁-C₆, more preferably C₁-C₄, most preferably C₁-C₃ alkylgroups. Where an alkyl moiety is said to be substituted, the alkylmoiety is preferably substituted by one to four substituents, mostpreferably by one to three substituents.

Alkylene groups can be in the form of a straight or branched chain andare, for example, —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—,—CH(CH₃)—CH₂—, or —CH(CH₂CH₃)—. The alkylene groups are preferablyC₁-C₃, more preferably C₁-C₂, most preferably C₁ alkylene groups. Wherean alkylene moiety is said to be substituted, the alkyl moiety ispreferably substituted by one to four substituents, most preferably byone to three substituents.

Alkenyl groups can be in the form of straight or branched chains, andcan be, where appropriate, of either the (E)- or (Z)-configuration.Examples are vinyl and allyl. The alkenyl groups are preferably C₂-C₆,more preferably C₂-C₄, most preferably C₂-C₃ alkenyl groups. Where analkenyl moiety is said to be substituted, the alkyl moiety is preferablysubstituted by one to four substituents, most preferably by one to threesubstituents.

Alkynyl groups can be in the form of straight or branched chains.Examples are ethynyl and propargyl. The alkynyl groups are preferablyC₂-C₆, more preferably C₂-C₄, most preferably C₂-C₃ alkynyl groups.Where an alkynyl moiety is said to be substituted, the alkyl moiety ispreferably substituted by one to four substituents, most preferably byone to three substituents.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such ashaloalkoxy-, haloalkylthio-, haloalkylsulfinyl- or haloalkylsulfonyl-)are alkyl groups which are substituted by one or more of the same ordifferent halogen atoms and are, for example, difluoromethyl,trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.

Haloalkenyl groups are alkenyl groups which are substituted by one ormore of the same or different halogen atoms and are, for example,2,2-difluoro-vinyl or 1,2-dichloro-2-fluoro-vinyl.

Haloalkynyl groups are alkynyl groups which are substituted by one ormore of the same or different halogen atoms and are, for example,1-chloro-prop-2-ynyl.

Cycloalkyl groups or carbocyclic rings can be in mono- or bi-cyclic formand are, for example, cyclopropyl, cyclobutyl, cyclohexyl andbicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are preferably C₃-C₈,more preferably C₃-C₆ cycloalkyl groups. Where a cycloalkyl moiety issaid to be substituted, the cycloalkyl moiety is preferably substitutedby one to four substituents, most preferably by one to threesubstituents.

Aryl groups (either alone or as part of a larger group, such asaryl-alkylene-) are aromatic ring systems which can be in mono-, bi- ortricyclic form. Examples of such rings include phenyl, naphthyl,anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyland naphthyl, phenyl being most preferred. Where an aryl moiety is saidto be substituted, the aryl moiety is preferably substituted by one tofour substituents, most preferably by one to three substituents.

Heteroaryl groups (either alone or as part of a larger group, such asheteroaryl-alkylene-) are aromatic ring systems containing at least oneheteroatom and consisting either of a single ring or of two or morefused rings. Preferably, single rings will contain up to threeheteroatoms and bicyclic systems up to four heteroatoms which willpreferably be chosen from nitrogen, oxygen and sulfur. Examples ofmonocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g. 1.2.4 triazoyl),furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, tetrazolyl and thiadiazolyl. Examples of bicyclic groupsinclude purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl,indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl.Monocyclic heteroaryl groups are preferred, pyridyl being mostpreferred. Where a heteroaryl moiety is said to be substituted, theheteroaryl moiety is preferably substituted by one to four substituents,most preferably by one to three substituents.

Heterocyclyl groups or heterocyclic rings (either alone or as part of alarger group, such as heterocyclyl-alkylene-) are defined to includeheteroaryl groups and in addition their unsaturated or partiallyunsaturated analogues. Examples of monocyclic groups include isoxazolyl,thietanyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl,dihydropyranyl, tetrahydropyranyl, dihydrothiophene, [1,3]dioxolanyl,piperidinyl, piperazinyl, [1,4]dioxanyl, morpholinyl, thiophene,oxetanyl, tetrahydropyranyl, 3-oxo-isoxazolidinyl-,2,5-dioxo-1-pyrrolidinyl-, 2-oxo-1-pyrrolidinyl-, 4-oxo-1,3-oxazinanyl,1-oxa-3,4-diazolyl, including their oxidised versions such as1-oxo-thietanyl and 1,1-dioxo-thietanyl, thiophene 1-oxide, thiophene1,1-dioxide, dihydrothiophene, dihydrothiophene 1-oxide, ordihydrothiophene 1,1-dioxide. Examples of bicyclic groups include2,3-dihydro-benzofuranyl, benzo[1,4]dioxolanyl, benzo[1,3]dioxolanyl,chromenyl, and 2,3-dihydro-benzo[1,4]dioxinyl. Where a heterocyclylmoiety is said to be substituted, the heterocyclyl moiety is preferablysubstituted by one to four substituents, most preferably by one to threesubstituents. Heterocyclyl groups (and heteroaryl groups) according tothe present invention do not contain adjacent oxygen atoms, adjacentsulphur atoms, or adjacent sulphur and oxygen atoms. Preferredheterocyclyl groups are thiophene, thiophene 1-oxide, thiophene1,1-dioxide, dihydrothiophene, dihydrothiophene 1-oxide,dihydrothiophene 1,1-dioxide, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, and tetrazoyl,

Leaving groups according to the invention include halogen,C₁-C₈alkylsulfonyloxy, C₁-C₈haloalkylsulfonyloxy, C₁-C₈arylsulfonyloxyor C₁-C₈arylsulfonyloxy substituted by one to five R¹¹, wherein each R¹¹is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen (aryl is preferably phenyl), andphosphonate esters (e.g. —OP(O)(OR)₂, wherein R is methyl or ethyl). Apreferred leaving group is halogen, in particular chloro or bromo.

Preferred definitions are, in any combination, as set out below.

Preferably A¹ is C—R⁵.

Preferably A², A³, A⁴ are each CH.

Preferably —B¹—B²—B³— is —C═N—O—.

Preferably R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, more preferably ethyl ortrifluoroethyl, even more preferably ethyl or 2,2,2-trifluoroethyl.

Preferably R² is chloro or bromo, more preferably chloro.

Preferably R³ is trifluoromethyl, difluoromethyl orchlorodifluoromethyl, most preferably trifluoromethyl.

Preferably R⁴ is group (B)

wherein X² is C—X⁴ or nitrogen (preferably C—X⁴); X¹, X³ and X⁴ areindependently hydrogen, halogen or trihalomethyl, e.g. wherein at leasttwo of X¹, X³ and X⁴ are not hydrogen.

Preferably R⁴ is 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-bromophenyl,3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl,3,5-dichloro-4-iodophenyl, 3,4,5-trifluorophenyl,3-chloro-5-bromophenyl, 3-chloro-5-fluorophenyl,3-chloro-5-(trifluoromethyl)phenyl, 3-bromo-5-(trifluoromethyl)phenyl,3,4-dichloro-5-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl,4-chloro-3,5-bis(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,2,6-dichloro-4-pyridyl, 2,6-bis(trifluoromethyl)-4-pyridyl,2-chloro-4-pyridyl-, 2-trifluoromethyl-4-pyridyl, more preferably3,5-dichloro-phenyl, 3-chloro-5-bromophenyl,3-chloro-5-(trifluoromethyl)phenyl, 3,5-dichloro-4-fluorophenyl,3,4,5-trichlorophenyl, 3,5-bis(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 2,6-dichloro-4-pyridyl,2,6-bis(trifluoromethyl)-4-pyridyl, 3,5-dichloro-4-bromophenyl,3-bromo-5-(trifluoromethyl)phenyl, 3,5-dibromophenyl, or3,4-dichlorophenyl, 2-chloro-4-pyridyl-, 2-trifluoromethyl-4-pyridyl,even more preferably 3,5-dichloro-phenyl, 3,5-dichloro-4-fluorophenyl,3,4,5-trichlorophenyl, 3-(trifluoromethyl)phenyl,3,5-bis(trifluoromethyl)phenyl, most preferably 3,5-dichloro-phenyl,3,5-dichloro-4-fluorophenyl, or 3,4,5-trichlorophenyl-. In one group ofcompounds R⁴ is 3,5-dichloro-phenyl. In one group of compounds R⁴ is3,5-dichloro-4-fluorophenyl-. In one group of compounds R⁴ is3,4,5-trichlorophenyl-. In one group of compounds R⁴ is3,5-bis(trifluoromethyl)phenyl.

Preferably each R⁵ is independently halogen, cyano, methyl, halomethyl,methoxy or halomethoxy, more preferably chloro, fluoro, cyano or methyl.

Preferably each R⁶ is independently halogen, C₁-C₈alkyl, C₁-C₈haloalkyl,C₁-C₈alkoxy, C₁-C₈haloalkoxy, C₁-C₈alkylthio, or C₁-C₈haloalkylthio,more preferably bromo, chloro, fluoro, trifluoromethyl, methoxy, ormethylthio, most preferably trifluoromethyl, fluoro or chloro.

Preferably R⁷ is hydroxy, ONa, OLi, OK, chloro or bromo, morepreferably, ONa, OLi or chloro.

Preferably R⁸ is hydroxy, chloro or bromo, more preferably chloro.

Preferably R⁹ is hydrogen or C₁-C₆alkyl, more preferably methyl.

Preferably each R¹⁰ is independently C₁-C₆alkyl, more preferablyC₁-C₄alkyl, most preferably t-butyl.

In one preferred embodiment the compounds of formula (I), (II) and (III)and (IV) are compounds wherein R¹ is ethyl or trifluoroethyl (preferably2,2,2-trifluoroethyl) and R² is chloro or bromo, preferably chloro.

In a further preferred embodiment the compound of formula (IV) is acompound wherein R¹ is ethyl or trifluoroethyl (preferably2,2,2-trifluoroethyl) and R² is chloro or bromo, preferably chloro.

In a further preferred embodiment the compounds of formula (I), (II),(V) and (VI) are compounds wherein R¹ is ethyl or trifluoroethyl(preferably 2,2,2-trifluoroethyl) and R⁷ is hydroxy, ONa, OLi or chloro.

In a further preferred embodiment the compounds of formula (I), (II) and(VI) are compounds wherein R¹ is ethyl, trifluoroethyl or phenyl.

In a further preferred embodiment the compounds of formula (VI) is acompound wherein R¹ is ethyl or trifluoroethyl (preferably2,2,2-trifluoroethyl)

In a further preferred embodiment the compounds of formula (VIII) and(XII) are compounds wherein

A¹ is C—R⁵;

A², A³, A⁴ are each CH;

R³ is trifluoromethyl, difluoromethyl or chlorodifluoromethyl;

X is chloro, bromo, cyano, formyl, acetyl, C(O)CH═C(R³)R⁴,C(O)CH₂C(OH)(R³)R⁴ or group (A) as defined above;

R⁴ is group (B) as defined above;

X² is C—X⁴ or nitrogen (preferably C—X⁴); X¹, X³ and X⁴ areindependently hydrogen, halogen or trihalomethyl;

each R⁵ is independently halogen, cyano, methyl, halomethyl, methoxy orhalomethoxy, more preferably chloro, fluoro, cyano or methyl.

In a further preferred embodiment the compounds of formula (VIII) and(XII) are compounds wherein

X is acetyl, C(O)CH═C(R³)R⁴, C(O)CH₂C(OH)(R³)R⁴ or group (A);

A¹ is C—R⁵;

A², A³, A⁴ are each CH;

X is group (A)

—B¹—B²—B³— is —C═N—O—, —C═N—CH₂—, —C═CH—O— or —N—CH₂—CH₂—, preferably—C═N—O—;

R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted by one tofive R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substituted by oneto five R¹¹;

R³ is trifluoromethyl, difluoromethyl or chlorodifluoromethyl;

R⁴ is group (B)

wherein X² is C—X⁴ or nitrogen, X¹, X³ and X⁴ are independentlyhydrogen, halogen or trihalomethyl,

R⁵ is halogen, cyano, methyl, halomethyl, methoxy or halomethoxy;

each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, cyano or halogen.

In one preferred embodiment the compounds of formula (IX) and (XIII) arecompounds wherein R⁹ is C₁-C₆alkyl.

In one preferred embodiment the compounds of formula (X) and (XIV) arecompounds wherein each R¹⁰ is C₁-C₆alkyl, preferably t-butyl.

In enriched mixtures of the invention, the molar proportion of thecompound of formula (I*), (III*), (IV*), (V*), and/or (VI*) in themixture is for example greater than 50%, e.g. at least 60, 70, 80, 90 orat least 95% of the total molar amount of the pair of enantiomers.

The following schemes describe the reactions of the invention in moredetail. The substituent definitions are the same as defined above.

Step a

Compounds of formula (I) can be prepared by reacting a compound offormula (III) with a compound of formula (II) or salt thereof. Suitablesalts of compounds of formula (II) include, but are not limited tohalides, organic acids, and sulphur based salts, e.g. chloride, oxalate,sulfate, trifluoroacetate, mesylate and bromide.

The reactions of compounds of formula (III) and II are preferablycarried out in the presence of a suitable base. Suitable bases include,but are not limited to nitrogen-based organic bases such as amines,pyridines and derivatives thereof, e.g. triethylamine,tri-n-propylamine, pyridine and diisopropylethylamine.

The reactions of compounds of III and II are preferably carried out inthe presence of a solvent. Suitable solvents include, but are notlimited to organic solvents, e.g. halogenated organic solvents oralcohols such as chloroform, dichloromethane, dichloroethane,monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene,methanol, ethanol, isopropanol, t-butanol, cyclohexanol, heptanol,octanol, or longer chain alcohols, and diethyleneglycol, preferablychloroform, dichloromethane, isopropyl alcohol and ethanol. It is alsopossible to conduct the reaction in a mixture of an organic solvent andwater.

The reaction can be carried out at a temperature from −20° C. to 100°C., preferably from 0° C. to 30° C. (e.g. no lower than −20° C.,preferably no lower than 0° C., e.g. no more than 100° C., preferably nomore than 30° C.).

The reactions of compounds of formula (III) and II are preferablycarried out in the presence of a catalyst. Suitable catalysts include,but are not limited to nucleophilic catalysts capable of promoting acyltransfer reactions such as 4-dialkylaminopyridines, N-alkylimidazoles,phosphines, imidazolylidene carbenes, 1,2-diamines, bicyclic amidines,isothioureas and guanidines, triazoles, suitable alcohols, iodide andcyanide salts, preferably 4-dimethylaminopyridine.

Step a-1

Compounds of formula (IV) can be prepared by reacting a compound offormula (III) with a compound of formula (II) or salt thereof asdescribed under step a.

The reaction is preferably carried out in the presence of a solvent.Suitable solvents include, but are not limited to polar organicsolvents, e.g. acetic acid, propanoic acid or longer chain carboxylicacids, trifluoroacetic acid, methanol, ethanol, isopropanol, t-butanol,cyclohenxanol, heptanol, octanol, or longer chain alcohols,trifluoroethanol, ethyleneglycol, acetonitrile and propionitrile,preferably acetic acid. It is also possible to conduct the reaction in amixture of organic solvents or in a mixture of organic solvents andwater.

The reaction is preferably carried out in the presence of a suitableacid. Suitable acids include, but are not limited to organic acids, e.gacetic acid, propanoic acid or longer chain carboxylic acids,trifluoroacetic acid. A preferred acid is acetic acid.

The reaction can be carried out at a temperature from −20° C. to 100°C., preferably from 0° C. to 30° C. (e.g. no lower than −20° C.,preferably no lower than 0° C., e.g. no more than 100° C., preferably nomore than 30° C.).

Depending on the conditions used, it may be advantageous to isolatecompound IV as the corresponding salt. The salt may be formed with anacid already present in the reaction mixture or formed by adding anadditional acid to the reaction mixture. Suitable acids include mineralacids and organic acids such as HCl, HBr, H₂SO₄, acetic acid andtrifluoroacetic acid.

Step a-2

Compounds of formula (I) can be prepared by treating a compound offormula (IV) or a salt thereof as described under step a-1 with a base.Suitable bases include carbonates, hydroxides, nitrogen-based organicbases such as amines, pyridines and derivatives thereof, e.g. Na₂CO₃,K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine and diisopropylethylamine.

The reaction is preferably carried out in the presence of a solvent.Suitable solvents include, but are not limited to organic solvents suchas diethylether, 1,2-dimethoxyethane, diethoxymethane, diglyme, t-butylmethyl ether, THF, 2-methyl-THF, dioxane; halogenated solvents such aschloroform, dichloromethane, dichloroethane, monochlorobenzene,dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketonessuch as ethyl acetate, acetone 2-butanone, methylisobutylketone; etherssuch as anisole, polar aprotic solvents such as acetonitrile,dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone,dimethylacetamide; and alcohols, such as methanol, ethanol, isopropanol,t-BuOH, cyclohexanol, heptanol, octanol, or longer chain alcohols, anddiethyleneglycol. Preferred organic solvents include tetrahydrofuran,dioxane and acetonitrile.

The reaction can be carried out at a temperature from −20° C. to 100°C., preferably from 0° C. to 30° C.

Compounds of formula (I) can be isolated in a free form or as saltsformed by adding an acid to compounds of formula (I) in a free baseform. Suitable acids include mineral acids and organic acids such asHCl, HBr, H₂SO₄, acetic acid and trifluoroacetic acid.

When compounds of formula (II) and formula (III) are reacted underacidic conditions as described for step a-1 a compound of formula (IV)is isolated. Treating the compound of formula (IV) in a compound underbasic conditions as described for step a-2 a compound of formula (I) isformed.

When compounds of formula (II) and formula (III) are reacted under basicconditions as described for step a intermediate compound of formula (IV)cannot be isolated and compound of formula (I) is formed directly.

Steps 1-1, 1-2 and 1-3

This is described under scheme 3 below. Steps a and 1-1, 1-2 and 1-3 canbe conducted in the same reaction vessel (one-pot reaction) withoutisolation of the compound of formula (I), e.g. when the solvent ischloroform. In other words, compounds of formula (VIII), (IX) and (X)can be prepared from the compound of formula (III) without isolation ofthe compound of formula (I) or (IV). Alternatively, steps a-2 and 1-1,1-2 and 1-3 can be conducted in the same reaction vessel (one-potreaction) without isolation of the compound of formula (I).

Step i-a

Compounds of formula (Va) can be prepared from compounds of formula (XI)by treatment with by phosgene or a derivative thereof e.g. diphosgene,triphosgene, ethyl chloroformate, benzylchloroformate, in the presenceof aqueous base following the similar procedure described in SyntheticComm 1993, 23, 2839, which is incorporated herein by reference.

Step i

Compounds of formula (VI) can be prepared by reacting a compound offormula (Va) with a compound of formula (II). Preferably the reactionincludes preparing the corresponding acid halide (preferably acidchloride) of the compound of formula (Va), compound (Vb), wherein R⁷ ishalogen, to facilitate the conversion to the compound of formula (VI).The acid halide, compound (Vb), wherein R⁷ is halogen, can be preparedfrom the compound of formula (Va) under conditions well known to theperson skilled in the art, such as by treatment with thionyl chloride,oxalyl chloride, phosgene, diphosgene or triphosgene.

Alternatively compound (Vb), wherein R⁷ is halogen, can be prepared froman alkali metal (Li, Na, K) salt of compound of formula (Va), compound(Vc), by treatment with oxalyl chloride, thionyl chloride, phosgene,diphosgene or triphosgene in the presence of a phase transfer catalyst.Suitable phase transfer catalysts include, but are not limited totetrabutylamonium chloride, tetrabutylamonium bromide,triethylbenzylamonium chloride, Aliquot® 336 and(1-hexadecyl)trimethylamomnium bromide

Alkali metal salts of compound of formula (V) where M is Li, Na or K,compounds Vc, can be prepared as shown in Scheme 2a.

Step iii and iv

Compounds of formula (Vc) where M is Li, Na or K can be prepared eitherby treating compounds of formula (XV) where R¹² is C₁-C₄ alkyl withLiOH, NaOH or KOH or by treating compounds of formula (XVI) where R¹³ isC₁-C₄ alkyl, benzyl or phenyl with LiOH, NaOH or KOH. Suitable solventsinclude but are not limited to alcohols such as ethanol, methanol andisopropanol; polar organic solvents such as acetonitrile, dioxane, THF,2-methyl-THF as well as water. Preferred solvents are ethanol andacetonitrile.

The reaction of the acid halide of compound of formula (V), compound(Vb), wherein R⁷ is halogen, with compounds of formula (II) arepreferably carried out in the presence of a base. Suitable basesinclude, but are not limited to carbonates, hydroxides, nitrogen-basedorganic bases such as amines, pyridines and derivatives thereof, e.g.triethylamine, tri-n-propylamine, pyridine, diisopropylethylamine,Na₂CO₃, NaHCO₃, NaOH and N-methyl morpholine.

The reaction of the acid halide of compound of formula (V), compound Vb,wherein R⁷ is halogen, with compounds of formula (II) are optionallycarried out in the presence of a nucleophilic catalyst. Suitablecatalysts include, but are not limited to nucleophilic catalysts such as4-dimethylaminopyridine.

Suitable solvents include, but are not limited to ethers, such asdiethylether, 1,2-dimethoxyethane, diethoxymethane, diglyme, t-butylmethyl ether, THF, 2-methyl-THF, dioxane; halogenated solvents such aschloroform, dichloromethane, dichloroethane, monochlorobenzene,dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketonessuch as ethyl acetate, acetone, 2-butanone, methylisobutylketone;anisole, polar aprotic solvents such as acetonitrile, dimethylsulfoxide,dimethylformamide, N-methylpyrrolidone and dimethylacetamide; orwater/biphasic systems (as is known in the so-called Schotten-Baumannconditions) as well as hydrocarbons, such as toluene and xylenes both aspure isomers and a mixture of isomers.

Compounds of formula (II) can be used as such or in the form of theirsalts with acids, for example HCl, HBr, trifluoroacetic acid, oxalicacid, sulfuric acids and methanesulfonic acid.

The reaction can be carried out at a temperature from −20° C. to 100°C., preferably from −10° C. to 30° C., in particular between −5° C. to+10° C.; More preferably the reaction can be carried out at atemperature from 0° C. to +10° C.

Alternatively, it is possible to conduct the reaction in a biphasicsystem comprising an organic solvent, preferably ethyl acetate,2-methyltetrahydrofuran, or dichloromethane, and an aqueous solvent,preferably a solution of sodium hydrogen carbonate or sodium carbonateor organic amine such as triethylamine or diisopropylethylamine.

Alternatively the reaction of the compound of formula (V) with thecompound of formula (II) can be carried out in the presence of acoupling reagent, such as N,N′-dicyclohexylcarbodiimide (“DCC”),1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (“EDC”) orbis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), in the presenceof a base, and optionally in the presence of a nucleophilic catalyst,such as hydroxybenzotriazole (“HOBT”).

Suitable bases include carbonates, hydroxides, nitrogen-based organicbases such as amines, pyridines and derivatives thereof, e.g. Na₂CO₃,K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine, N-methyl morpholine anddiisopropylethylamine.

Examples of suitable solvents include ethers, such as diethylether,1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether,THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform,dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene,trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethylacetate, acetone, 2-butanone, methylisobutylketone; anisole, polaraprotic solvents such as acetonitrile, dimethylsulfoxide,dimethylformamide, N-methylpyrrolidone, dimethylacetamide, hydrocarbonssuch as toluene and xylenes both as pure isomers and as a mixture ofisomers. Preferred solvents are dichloromethane, dichloroethane, ethylacetate, THF, 2-methyl-THF or dioxane.

The reaction can be carried out at a temperature from −20° C. to 100°C., preferably from −10° C. to 30° C., in particular from −5° C. to +5°C., more preferably from 0° C. to +5° C.

Step ii

Compounds of formula (I) can be prepared by treating compounds offormula (VI) with a base. Suitable bases include carbonates, hydroxides,nitrogen-based organic bases such as amines, pyridines and derivativesthereof, e.g. Na₂CO₃, K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine,N-methyl morpholine and diisopropylethylamine.

It is possible to conduct the reaction in a mixture of an organicsolvent with water or in water alone. Preferably the reaction includesthe presence of water.

Examples of organic solvents include ethers, such as diethylether,1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether,THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform,dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene,trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethylacetate, acetone 2-butanone, methylisobutylketone; anisole, polaraprotic solvents such as acetonitrile, dimethylsulfoxide,dimethylformamide, N-methylpyrrolidone, dimethylacetamide; and alcohols,such as methanol, ethanol, isopropanol, t-BuOH, cyclohenxanol, heptanol,octanol, or longer chain alcohols, and diethyleneglycol; and aromatichydrocarbons such as toluene and xylenes both as pure isomers and as amixture of isomers. Preferred organic solvents include tetrahydrofuran,2-methyl tetrahydrofuran, dioxane, acetonitrile, DMF.

Alternatively it is possible to conduct the reaction in a biphasicsystem comprising an organic solvent as described above under step iithat are immiscible with water, preferably ethyl acetate, 2-methyltetrahydrofuran or dichloromethane, and an aqueous solvent, preferably asolution of sodium hydrogen carbonate or sodium carbonate or an organicamine such as triethylamine or diisopropylethylamine. It can also bepossible to conduct the reaction in aqueous solvent without addition ofbase.

The reaction can be carried out at a temperature from 0° C. to 100° C.,preferably from 20° C. to 70° C., in particular at 50° C. (e.g. no lowerthan 0° C., preferably no lower than 20° C., e.g. no more than 100° C.,preferably no more than 70° C.). A temperature no lower than 20° C. ispreferred to reduce reaction times.

Compounds of formula (I) can be isolated in a free form or as saltsformed by adding an acid to compounds of formula (I) in a free baseform. Suitable acids include mineral acids and organic acids such asHCl, HBr, H₂SO₄, acetic acid, methanesulfonic acids,p-methylphenylsulfonic acids, oxalic acid and trifluoroacetic acid.

Steps 1-1, 1-2 and 1-3

This is described under Scheme 3 below. Steps i, ii and 1-1, 1-2 and 1-3can be conducted in the same reaction vessel (one-pot reaction) withoutisolation of the compound of formula (I). In other words, compound offormula (VIII), (IX) and (X) can be prepared from the compound offormula (V) without isolation of the compound of formula (VI) or (I).

Step 1-1

Compounds of formula (VIII) can be prepared by reacting a compound offormula (I) with a compound of formula (XII) wherein the substituentsare defined as herein disclosed. When R⁸ is hydroxy such reactions areusually carried out in the presence of a coupling reagent, such asN,N′-dicyclohexylcarbodiimide (“DCC”),1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (“EDC”) orbis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), in the presenceof a base, and optionally in the presence of a nucleophilic catalyst,such as hydroxybenzotriazole (“HOBT”).

Suitable bases include carbonates, hydroxides, nitrogen-based organicbases such as amines, pyridines and derivatives thereof, e.g. Na₂CO₃,K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine, N-methyl morpholine anddiisopropylethylamine.

Suitable solvents include, but are not limited to polar organicsolvents, e.g. halogenated organic solvents or ethers such aschloroform, dichloromethane, dichloroethane, monochlorobenzene,dichlorobenzene, trichlorobenzene, 4-fluorotoluene, THF, 2-methyl THF,dioxane, dimethoxyethane, toluene, acetonitrile and xylenes preferablychloroform, dichloromethane or THF.

When R⁸ is chloro such reactions are usually carried out in the presenceof a base, and optionally in the presence of a nucleophilic catalystsuch as 4-dimethylamino pyridine (“DMAP”).

Suitable bases include carbonates, hydroxides, nitrogen-based organicbases such as amines, pyridines and derivatives thereof, e.g. Na₂CO₃,K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine, N-methyl morpholine anddiisopropylethylamine.

Examples of solvents include ethers, such as diethylether,1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether,THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform,dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene,trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethylacetate, acetone 2-butanone, methylisobutylketone; anisole, polaraprotic solvents such as acetonitrile, dimethylsulfoxide,dimethylformamide, N-methylpyrrolidone and dimethylacetamide, aromatichydrocarbons such as toluene and xylenes both as pure isomers and as amixture of isomers. Preferred solvents are dichloromethane,dichloroethane, ethyl acetate, THF, 2-methyl tetrahydrofuran or dioxane.

Alternatively, it is possible to conduct the reaction in a biphasicsystem comprising an organic solvent, preferably ethyl acetate, toluene,xylenes as single isomers or as a mixture of isomers or dichloromethane,and an aqueous solvent, preferably a solution of sodium hydrogencarbonate or sodium carbonate or an organic amine such as triethylamineor diisopropylethyl amine.

The reaction can be carried out at a temperature from 0° C. to 100° C.,preferably from 15° C. to 30° C., in particular at ambient temperature(e.g. no lower than 0° C., preferably no lower than 15° C., e.g. no morethan 100° C., preferably no more than 30° C.).

Step 1-2

Compounds of formula (IX), wherein R⁹ is as defined above, can beprepared under the conditions as described under 1-1 by reacting acompound of formula (I) with a compound of formula (XIII) wherein thesubstituents are defined as herein disclosed.

Step 1-3

Compounds of formula X can be prepared by reacting compounds of formula(I) with a compound according to formula (XIVa) or (XIVb). An example ofa compound according to formula (XIVa) di-tert-butyl dicarbonate in apresence of base. Suitable bases include carbonates, hydroxides,nitrogen-based organic bases such as amines, pyridines and derivativesthereof, e.g. Na₂CO₃, K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine,N-methyl morpholine and diisopropylethylamine.

Examples of solvents include ethers, such as diethylether,1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether,THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform,dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene,trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethylacetate, acetone 2-butanone, methylisobutylketone; anisole, polaraprotic solvents such as acetonitrile, dimethylsulfoxide,dimethylformamide, N-methylpyrrolidone, dimethylacetamide; and alcohols,such as methanol, ethanol, isopropanol, t-BuOH, cyclohenxanol, heptanol,octanol, or longer chain alcohols, and diethyleneglycol; aromatichydrocarbons such as toluene and xylenes both as pure isomers and as amixture of isomers. Preferred solvents are dichloromethane,dichloroethane, ethyl acetate, THF, or dioxane. Alternatively it ispossible to conduct the reaction in the mixture of these solvents andwater.

Alternatively it is possible to conduct the reaction in a biphasicsystem comprising an organic solvent as described above under 1-3,preferably ethyl acetate, toluene, xylene or dichloromethane, and anaqueous base, preferably a solution of sodium hydrogen carbonate orsodium carbonate.

The reaction can be carried out at a temperature from −20° C. to 100°C., preferably from 0° C. to 40° C., in particular at ambienttemperature (e.g. no lower than −20° C., preferably no lower than 0° C.,e.g. no more than 100° C., preferably no more than 40° C.).

Scheme 4 illustrates how compounds of formula (VIII) may be reacted toproduce insecticidally active compounds as described in WO2011/067272and WO2013/069731, with reaction conditions described therein. Othermethods of arriving at compounds of formula (Ville) using the presentinvention will be apparent to the person skilled in the art, and arealso described in WO2011/067272.

Possible combinations of substituents are shown in Table 1.

TABLE 1 X1 X4 X3 R5 R1 1 Br H H CH3 CH2CF3 2 Cl H H CH3 CH2CF3 3 F H HCH3 CH2CF3 4 CF3 H H CH3 CH2CF3 5 H Br H CH3 CH2CF3 6 Br Br H CH3 CH2CF37 Cl Br H CH3 CH2CF3 8 F Br H CH3 CH2CF3 9 CF3 Br H CH3 CH2CF3 10 H Cl HCH3 CH2CF3 11 Br Cl H CH3 CH2CF3 12 Cl Cl H CH3 CH2CF3 13 F Cl H CH3CH2CF3 14 CF3 Cl H CH3 CH2CF3 15 H F H CH3 CH2CF3 16 Br F H CH3 CH2CF317 Cl F H CH3 CH2CF3 18 F F H CH3 CH2CF3 19 CF3 F H CH3 CH2CF3 20 H H BrCH3 CH2CF3 21 Br H Br CH3 CH2CF3 22 Cl H Br CH3 CH2CF3 23 F H Br CH3CH2CF3 24 CF3 H Br CH3 CH2CF3 25 H Br Br CH3 CH2CF3 26 Br Br Br CH3CH2CF3 27 Cl Br Br CH3 CH2CF3 28 F Br Br CH3 CH2CF3 29 CF3 Br Br CH3CH2CF3 30 H Cl Br CH3 CH2CF3 31 Br Cl Br CH3 CH2CF3 32 Cl Cl Br CH3CH2CF3 33 F Cl Br CH3 CH2CF3 34 CF3 Cl Br CH3 CH2CF3 35 H F Br CH3CH2CF3 36 Br F Br CH3 CH2CF3 37 Cl F Br CH3 CH2CF3 38 F F Br CH3 CH2CF339 CF3 F Br CH3 CH2CF3 40 H H Cl CH3 CH2CF3 41 Br H Cl CH3 CH2CF3 42 ClH Cl CH3 CH2CF3 43 F H Cl CH3 CH2CF3 44 CF3 H Cl CH3 CH2CF3 45 H Br ClCH3 CH2CF3 46 Br Br Cl CH3 CH2CF3 47 Cl Br Cl CH3 CH2CF3 48 F Br Cl CH3CH2CF3 49 CF3 Br Cl CH3 CH2CF3 50 H Cl Cl CH3 CH2CF3 51 Br Cl Cl CH3CH2CF3 52 Cl Cl Cl CH3 CH2CF3 53 F Cl Cl CH3 CH2CF3 54 CF3 Cl Cl CH3CH2CF3 55 H F Cl CH3 CH2CF3 56 Br F Cl CH3 CH2CF3 57 Cl F Cl CH3 CH2CF358 F F Cl CH3 CH2CF3 59 CF3 F Cl CH3 CH2CF3 60 H H F CH3 CH2CF3 61 Br HF CH3 CH2CF3 62 Cl H F CH3 CH2CF3 63 F H F CH3 CH2CF3 64 CF3 H F CH3CH2CF3 65 H Br F CH3 CH2CF3 66 Br Br F CH3 CH2CF3 67 Cl Br F CH3 CH2CF368 F Br F CH3 CH2CF3 69 CF3 Br F CH3 CH2CF3 70 H Cl F CH3 CH2CF3 71 BrCl F CH3 CH2CF3 72 Cl Cl F CH3 CH2CF3 73 F Cl F CH3 CH2CF3 74 CF3 Cl FCH3 CH2CF3 75 H F F CH3 CH2CF3 76 Br F F CH3 CH2CF3 77 Cl F F CH3 CH2CF378 F F F CH3 CH2CF3 79 CF3 F F CH3 CH2CF3 80 H H CF3 CH3 CH2CF3 81 Br HCF3 CH3 CH2CF3 82 Cl H CF3 CH3 CH2CF3 83 F H CF3 CH3 CH2CF3 84 CF3 H CF3CH3 CH2CF3 85 H Br CF3 CH3 CH2CF3 86 Br Br CF3 CH3 CH2CF3 87 Cl Br CF3CH3 CH2CF3 88 F Br CF3 CH3 CH2CF3 89 CF3 Br CF3 CH3 CH2CF3 90 H Cl CF3CH3 CH2CF3 91 Br Cl CF3 CH3 CH2CF3 92 Cl Cl CF3 CH3 CH2CF3 93 F Cl CF3CH3 CH2CF3 94 CF3 Cl CF3 CH3 CH2CF3 95 H F CF3 CH3 CH2CF3 96 Br F CF3CH3 CH2CF3 97 Cl F CF3 CH3 CH2CF3 98 F F CF3 CH3 CH2CF3 99 CF3 F CF3 CH3CH2CF3 100 Br H H Br CH2CF3 101 Cl H H Br CH2CF3 102 F H H Br CH2CF3 103CF3 H H Br CH2CF3 104 H Br H Br CH2CF3 105 Br Br H Br CH2CF3 106 Cl Br HBr CH2CF3 107 F Br H Br CH2CF3 108 CF3 Br H Br CH2CF3 109 H Cl H BrCH2CF3 110 Br Cl H Br CH2CF3 111 Cl Cl H Br CH2CF3 112 F Cl H Br CH2CF3113 CF3 Cl H Br CH2CF3 114 H F H Br CH2CF3 115 Br F H Br CH2CF3 116 Cl FH Br CH2CF3 117 F F H Br CH2CF3 118 CF3 F H Br CH2CF3 119 H H Br BrCH2CF3 120 Br H Br Br CH2CF3 121 Cl H Br Br CH2CF3 122 F H Br Br CH2CF3123 CF3 H Br Br CH2CF3 124 H Br Br Br CH2CF3 125 Br Br Br Br CH2CF3 126Cl Br Br Br CH2CF3 127 F Br Br Br CH2CF3 128 CF3 Br Br Br CH2CF3 129 HCl Br Br CH2CF3 130 Br Cl Br Br CH2CF3 131 Cl Cl Br Br CH2CF3 132 F ClBr Br CH2CF3 133 CF3 Cl Br Br CH2CF3 134 H F Br Br CH2CF3 135 Br F Br BrCH2CF3 136 Cl F Br Br CH2CF3 137 F F Br Br CH2CF3 138 CF3 F Br Br CH2CF3139 H H Cl Br CH2CF3 140 Br H Cl Br CH2CF3 141 Cl H Cl Br CH2CF3 142 F HCl Br CH2CF3 143 CF3 H Cl Br CH2CF3 144 H Br Cl Br CH2CF3 145 Br Br ClBr CH2CF3 146 Cl Br Cl Br CH2CF3 147 F Br Cl Br CH2CF3 148 CF3 Br Cl BrCH2CF3 149 H Cl Cl Br CH2CF3 150 Br Cl Cl Br CH2CF3 151 Cl Cl Cl BrCH2CF3 152 F Cl Cl Br CH2CF3 153 CF3 Cl Cl Br CH2CF3 154 H F Cl BrCH2CF3 155 Br F Cl Br CH2CF3 156 Cl F Cl Br CH2CF3 157 F F Cl Br CH2CF3158 CF3 F Cl Br CH2CF3 159 H H F Br CH2CF3 160 Br H F Br CH2CF3 161 Cl HF Br CH2CF3 162 F H F Br CH2CF3 163 CF3 H F Br CH2CF3 164 H Br F BrCH2CF3 165 Br Br F Br CH2CF3 166 Cl Br F Br CH2CF3 167 F Br F Br CH2CF3168 CF3 Br F Br CH2CF3 169 H Cl F Br CH2CF3 170 Br Cl F Br CH2CF3 171 ClCl F Br CH2CF3 172 F Cl F Br CH2CF3 173 CF3 Cl F Br CH2CF3 174 H F F BrCH2CF3 175 Br F F Br CH2CF3 176 Cl F F Br CH2CF3 177 F F F Br CH2CF3 178CF3 F F Br CH2CF3 179 H H CF3 Br CH2CF3 180 Br H CF3 Br CH2CF3 181 Cl HCF3 Br CH2CF3 182 F H CF3 Br CH2CF3 183 CF3 H CF3 Br CH2CF3 184 H Br CF3Br CH2CF3 185 Br Br CF3 Br CH2CF3 186 Cl Br CF3 Br CH2CF3 187 F Br CF3Br CH2CF3 188 CF3 Br CF3 Br CH2CF3 189 H Cl CF3 Br CH2CF3 190 Br Cl CF3Br CH2CF3 191 Cl Cl CF3 Br CH2CF3 192 F Cl CF3 Br CH2CF3 193 CF3 Cl CF3Br CH2CF3 194 H F CF3 Br CH2CF3 195 Br F CF3 Br CH2CF3 196 Cl F CF3 BrCH2CF3 197 F F CF3 Br CH2CF3 198 CF3 F CF3 Br CH2CF3 199 Br H H ClCH2CF3 200 Cl H H Cl CH2CF3 201 F H H Cl CH2CF3 202 CF3 H H Cl CH2CF3203 H Br H Cl CH2CF3 204 Br Br H Cl CH2CF3 205 Cl Br H Cl CH2CF3 206 FBr H Cl CH2CF3 207 CF3 Br H Cl CH2CF3 208 H Cl H Cl CH2CF3 209 Br Cl HCl CH2CF3 210 Cl Cl H Cl CH2CF3 211 F Cl H Cl CH2CF3 212 CF3 Cl H ClCH2CF3 213 H F H Cl CH2CF3 214 Br F H Cl CH2CF3 215 Cl F H Cl CH2CF3 216F F H Cl CH2CF3 217 CF3 F H Cl CH2CF3 218 H H Br Cl CH2CF3 219 Br H BrCl CH2CF3 220 Cl H Br Cl CH2CF3 221 F H Br Cl CH2CF3 222 CF3 H Br ClCH2CF3 223 H Br Br Cl CH2CF3 224 Br Br Br Cl CH2CF3 225 Cl Br Br ClCH2CF3 226 F Br Br Cl CH2CF3 227 CF3 Br Br Cl CH2CF3 228 H Cl Br ClCH2CF3 229 Br Cl Br Cl CH2CF3 230 Cl Cl Br Cl CH2CF3 231 F Cl Br ClCH2CF3 232 CF3 Cl Br Cl CH2CF3 233 H F Br Cl CH2CF3 234 Br F Br ClCH2CF3 235 Cl F Br Cl CH2CF3 236 F F Br Cl CH2CF3 237 CF3 F Br Cl CH2CF3238 H H Cl Cl CH2CF3 239 Br H Cl Cl CH2CF3 240 Cl H Cl Cl CH2CF3 241 F HCl Cl CH2CF3 242 CF3 H Cl Cl CH2CF3 243 H Br Cl Cl CH2CF3 244 Br Br ClCl CH2CF3 245 Cl Br Cl Cl CH2CF3 246 F Br Cl Cl CH2CF3 247 CF3 Br Cl ClCH2CF3 248 H Cl Cl Cl CH2CF3 249 Br Cl Cl Cl CH2CF3 250 Cl Cl Cl ClCH2CF3 251 F Cl Cl Cl CH2CF3 252 CF3 Cl Cl Cl CH2CF3 253 H F Cl ClCH2CF3 254 Br F Cl Cl CH2CF3 255 Cl F Cl Cl CH2CF3 256 F F Cl Cl CH2CF3257 CF3 F Cl Cl CH2CF3 258 H H F Cl CH2CF3 259 Br H F Cl CH2CF3 260 Cl HF Cl CH2CF3 261 F H F Cl CH2CF3 262 CF3 H F Cl CH2CF3 263 H Br F ClCH2CF3 264 Br Br F Cl CH2CF3 265 Cl Br F Cl CH2CF3 266 F Br F Cl CH2CF3267 CF3 Br F Cl CH2CF3 268 H Cl F Cl CH2CF3 269 Br Cl F Cl CH2CF3 270 ClCl F Cl CH2CF3 271 F Cl F Cl CH2CF3 272 CF3 Cl F Cl CH2CF3 273 H F F ClCH2CF3 274 Br F F Cl CH2CF3 275 Cl F F Cl CH2CF3 276 F F F Cl CH2CF3 277CF3 F F Cl CH2CF3 278 H H CF3 Cl CH2CF3 279 Br H CF3 Cl CH2CF3 280 Cl HCF3 Cl CH2CF3 281 F H CF3 Cl CH2CF3 282 CF3 H CF3 Cl CH2CF3 283 H Br CF3Cl CH2CF3 284 Br Br CF3 Cl CH2CF3 285 Cl Br CF3 Cl CH2CF3 286 F Br CF3Cl CH2CF3 287 CF3 Br CF3 Cl CH2CF3 288 H Cl CF3 Cl CH2CF3 289 Br Cl CF3Cl CH2CF3 290 Cl Cl CF3 Cl CH2CF3 291 F Cl CF3 Cl CH2CF3 292 CF3 Cl CF3Cl CH2CF3 293 H F CF3 Cl CH2CF3 294 Br F CF3 Cl CH2CF3 295 Cl F CF3 ClCH2CF3 296 F F CF3 Cl CH2CF3 297 CF3 F CF3 Cl CH2CF3 298 Br H H CF3CH2CF3 299 Cl H H CF3 CH2CF3 300 F H H CF3 CH2CF3 301 CF3 H H CF3 CH2CF3302 H Br H CF3 CH2CF3 303 Br Br H CF3 CH2CF3 304 Cl Br H CF3 CH2CF3 305F Br H CF3 CH2CF3 306 CF3 Br H CF3 CH2CF3 307 H Cl H CF3 CH2CF3 308 BrCl H CF3 CH2CF3 309 Cl Cl H CF3 CH2CF3 310 F Cl H CF3 CH2CF3 311 CF3 ClH CF3 CH2CF3 312 H F H CF3 CH2CF3 313 Br F H CF3 CH2CF3 314 Cl F H CF3CH2CF3 315 F F H CF3 CH2CF3 316 CF3 F H CF3 CH2CF3 317 H H Br CF3 CH2CF3318 Br H Br CF3 CH2CF3 319 Cl H Br CF3 CH2CF3 320 F H Br CF3 CH2CF3 321CF3 H Br CF3 CH2CF3 322 H Br Br CF3 CH2CF3 323 Br Br Br CF3 CH2CF3 324Cl Br Br CF3 CH2CF3 325 F Br Br CF3 CH2CF3 326 CF3 Br Br CF3 CH2CF3 327H Cl Br CF3 CH2CF3 328 Br Cl Br CF3 CH2CF3 329 Cl Cl Br CF3 CH2CF3 330 FCl Br CF3 CH2CF3 331 CF3 Cl Br CF3 CH2CF3 332 H F Br CF3 CH2CF3 333 Br FBr CF3 CH2CF3 334 Cl F Br CF3 CH2CF3 335 F F Br CF3 CH2CF3 336 CF3 F BrCF3 CH2CF3 337 H H Cl CF3 CH2CF3 338 Br H Cl CF3 CH2CF3 339 Cl H Cl CF3CH2CF3 340 F H Cl CF3 CH2CF3 341 CF3 H Cl CF3 CH2CF3 342 H Br Cl CF3CH2CF3 343 Br Br Cl CF3 CH2CF3 344 Cl Br Cl CF3 CH2CF3 345 F Br Cl CF3CH2CF3 346 CF3 Br Cl CF3 CH2CF3 347 H Cl Cl CF3 CH2CF3 348 Br Cl Cl CF3CH2CF3 349 Cl Cl Cl CF3 CH2CF3 350 F Cl Cl CF3 CH2CF3 351 CF3 Cl Cl CF3CH2CF3 352 H F Cl CF3 CH2CF3 353 Br F Cl CF3 CH2CF3 354 Cl F Cl CF3CH2CF3 355 F F Cl CF3 CH2CF3 356 CF3 F Cl CF3 CH2CF3 357 H H F CF3CH2CF3 358 Br H F CF3 CH2CF3 359 Cl H F CF3 CH2CF3 360 F H F CF3 CH2CF3361 CF3 H F CF3 CH2CF3 362 H Br F CF3 CH2CF3 363 Br Br F CF3 CH2CF3 364Cl Br F CF3 CH2CF3 365 F Br F CF3 CH2CF3 366 CF3 Br F CF3 CH2CF3 367 HCl F CF3 CH2CF3 368 Br Cl F CF3 CH2CF3 369 Cl Cl F CF3 CH2CF3 370 F Cl FCF3 CH2CF3 371 CF3 Cl F CF3 CH2CF3 372 H F F CF3 CH2CF3 373 Br F F CF3CH2CF3 374 Cl F F CF3 CH2CF3 375 F F F CF3 CH2CF3 376 CF3 F F CF3 CH2CF3377 H H CF3 CF3 CH2CF3 378 Br H CF3 CF3 CH2CF3 379 Cl H CF3 CF3 CH2CF3380 F H CF3 CF3 CH2CF3 381 CF3 H CF3 CF3 CH2CF3 382 H Br CF3 CF3 CH2CF3383 Br Br CF3 CF3 CH2CF3 384 Cl Br CF3 CF3 CH2CF3 385 F Br CF3 CF3CH2CF3 386 CF3 Br CF3 CF3 CH2CF3 387 H Cl CF3 CF3 CH2CF3 388 Br Cl CF3CF3 CH2CF3 389 Cl Cl CF3 CF3 CH2CF3 390 F Cl CF3 CF3 CH2CF3 391 CF3 ClCF3 CF3 CH2CF3 392 H F CF3 CF3 CH2CF3 393 Br F CF3 CF3 CH2CF3 394 Cl FCF3 CF3 CH2CF3 395 F F CF3 CF3 CH2CF3 396 CF3 F CF3 CF3 CH2CF3 397 Br HH CH3 CH2CH3 398 Cl H H CH3 CH2CH3 399 F H H CH3 CH2CH3 400 CF3 H H CH3CH2CH3 401 H Br H CH3 CH2CH3 402 Br Br H CH3 CH2CH3 403 Cl Br H CH3CH2CH3 404 F Br H CH3 CH2CH3 405 CF3 Br H CH3 CH2CH3 406 H Cl H CH3CH2CH3 407 Br Cl H CH3 CH2CH3 408 Cl Cl H CH3 CH2CH3 409 F Cl H CH3CH2CH3 410 CF3 Cl H CH3 CH2CH3 411 H F H CH3 CH2CH3 412 Br F H CH3CH2CH3 413 Cl F H CH3 CH2CH3 414 F F H CH3 CH2CH3 415 CF3 F H CH3 CH2CH3416 H H Br CH3 CH2CH3 417 Br H Br CH3 CH2CH3 418 Cl H Br CH3 CH2CH3 419F H Br CH3 CH2CH3 420 CF3 H Br CH3 CH2CH3 421 H Br Br CH3 CH2CH3 422 BrBr Br CH3 CH2CH3 423 Cl Br Br CH3 CH2CH3 424 F Br Br CH3 CH2CH3 425 CF3Br Br CH3 CH2CH3 426 H Cl Br CH3 CH2CH3 427 Br Cl Br CH3 CH2CH3 428 ClCl Br CH3 CH2CH3 429 F Cl Br CH3 CH2CH3 430 CF3 Cl Br CH3 CH2CH3 431 H FBr CH3 CH2CH3 432 Br F Br CH3 CH2CH3 433 Cl F Br CH3 CH2CH3 434 F F BrCH3 CH2CH3 435 CF3 F Br CH3 CH2CH3 436 H H Cl CH3 CH2CH3 437 Br H Cl CH3CH2CH3 438 Cl H Cl CH3 CH2CH3 439 F H Cl CH3 CH2CH3 440 CF3 H Cl CH3CH2CH3 441 H Br Cl CH3 CH2CH3 442 Br Br Cl CH3 CH2CH3 443 Cl Br Cl CH3CH2CH3 444 F Br Cl CH3 CH2CH3 445 CF3 Br Cl CH3 CH2CH3 446 H Cl Cl CH3CH2CH3 447 Br Cl Cl CH3 CH2CH3 448 Cl Cl Cl CH3 CH2CH3 449 F Cl Cl CH3CH2CH3 450 CF3 Cl Cl CH3 CH2CH3 451 H F Cl CH3 CH2CH3 452 Br F Cl CH3CH2CH3 453 Cl F Cl CH3 CH2CH3 454 F F Cl CH3 CH2CH3 455 CF3 F Cl CH3CH2CH3 456 H H F CH3 CH2CH3 457 Br H F CH3 CH2CH3 458 Cl H F CH3 CH2CH3459 F H F CH3 CH2CH3 460 CF3 H F CH3 CH2CH3 461 H Br F CH3 CH2CH3 462 BrBr F CH3 CH2CH3 463 Cl Br F CH3 CH2CH3 464 F Br F CH3 CH2CH3 465 CF3 BrF CH3 CH2CH3 466 H Cl F CH3 CH2CH3 467 Br Cl F CH3 CH2CH3 468 Cl Cl FCH3 CH2CH3 469 F Cl F CH3 CH2CH3 470 CF3 Cl F CH3 CH2CH3 471 H F F CH3CH2CH3 472 Br F F CH3 CH2CH3 473 Cl F F CH3 CH2CH3 474 F F F CH3 CH2CH3475 CF3 F F CH3 CH2CH3 476 H H CF3 CH3 CH2CH3 477 Br H CF3 CH3 CH2CH3478 Cl H CF3 CH3 CH2CH3 479 F H CF3 CH3 CH2CH3 480 CF3 H CF3 CH3 CH2CH3481 H Br CF3 CH3 CH2CH3 482 Br Br CF3 CH3 CH2CH3 483 Cl Br CF3 CH3CH2CH3 484 F Br CF3 CH3 CH2CH3 485 CF3 Br CF3 CH3 CH2CH3 486 H Cl CF3CH3 CH2CH3 487 Br Cl CF3 CH3 CH2CH3 488 Cl Cl CF3 CH3 CH2CH3 489 F ClCF3 CH3 CH2CH3 490 CF3 Cl CF3 CH3 CH2CH3 491 H F CF3 CH3 CH2CH3 492 Br FCF3 CH3 CH2CH3 493 Cl F CF3 CH3 CH2CH3 494 F F CF3 CH3 CH2CH3 495 CF3 FCF3 CH3 CH2CH3 496 Br H H Br CH2CH3 497 Cl H H Br CH2CH3 498 F H H BrCH2CH3 499 CF3 H H Br CH2CH3 500 H Br H Br CH2CH3 501 Br Br H Br CH2CH3502 Cl Br H Br CH2CH3 503 F Br H Br CH2CH3 504 CF3 Br H Br CH2CH3 505 HCl H Br CH2CH3 506 Br Cl H Br CH2CH3 507 Cl Cl H Br CH2CH3 508 F Cl H BrCH2CH3 509 CF3 Cl H Br CH2CH3 510 H F H Br CH2CH3 511 Br F H Br CH2CH3512 Cl F H Br CH2CH3 513 F F H Br CH2CH3 514 CF3 F H Br CH2CH3 515 H HBr Br CH2CH3 516 Br H Br Br CH2CH3 517 Cl H Br Br CH2CH3 518 F H Br BrCH2CH3 519 CF3 H Br Br CH2CH3 520 H Br Br Br CH2CH3 521 Br Br Br BrCH2CH3 522 Cl Br Br Br CH2CH3 523 F Br Br Br CH2CH3 524 CF3 Br Br BrCH2CH3 525 H Cl Br Br CH2CH3 526 Br Cl Br Br CH2CH3 527 Cl Cl Br BrCH2CH3 528 F Cl Br Br CH2CH3 529 CF3 Cl Br Br CH2CH3 530 H F Br BrCH2CH3 531 Br F Br Br CH2CH3 532 Cl F Br Br CH2CH3 533 F F Br Br CH2CH3534 CF3 F Br Br CH2CH3 535 H H Cl Br CH2CH3 536 Br H Cl Br CH2CH3 537 ClH Cl Br CH2CH3 538 F H Cl Br CH2CH3 539 CF3 H Cl Br CH2CH3 540 H Br ClBr CH2CH3 541 Br Br Cl Br CH2CH3 542 Cl Br Cl Br CH2CH3 543 F Br Cl BrCH2CH3 544 CF3 Br Cl Br CH2CH3 545 H Cl Cl Br CH2CH3 546 Br Cl Cl BrCH2CH3 547 Cl Cl Cl Br CH2CH3 548 F Cl Cl Br CH2CH3 549 CF3 Cl Cl BrCH2CH3 550 H F Cl Br CH2CH3 551 Br F Cl Br CH2CH3 552 Cl F Cl Br CH2CH3553 F F Cl Br CH2CH3 554 CF3 F Cl Br CH2CH3 555 H H F Br CH2CH3 556 Br HF Br CH2CH3 557 Cl H F Br CH2CH3 558 F H F Br CH2CH3 559 CF3 H F BrCH2CH3 560 H Br F Br CH2CH3 561 Br Br F Br CH2CH3 562 Cl Br F Br CH2CH3563 F Br F Br CH2CH3 564 CF3 Br F Br CH2CH3 565 H Cl F Br CH2CH3 566 BrCl F Br CH2CH3 567 Cl Cl F Br CH2CH3 568 F Cl F Br CH2CH3 569 CF3 Cl FBr CH2CH3 570 H F F Br CH2CH3 571 Br F F Br CH2CH3 572 Cl F F Br CH2CH3573 F F F Br CH2CH3 574 CF3 F F Br CH2CH3 575 H H CF3 Br CH2CH3 576 Br HCF3 Br CH2CH3 577 Cl H CF3 Br CH2CH3 578 F H CF3 Br CH2CH3 579 CF3 H CF3Br CH2CH3 580 H Br CF3 Br CH2CH3 581 Br Br CF3 Br CH2CH3 582 Cl Br CF3Br CH2CH3 583 F Br CF3 Br CH2CH3 584 CF3 Br CF3 Br CH2CH3 585 H Cl CF3Br CH2CH3 586 Br Cl CF3 Br CH2CH3 587 Cl Cl CF3 Br CH2CH3 588 F Cl CF3Br CH2CH3 589 CF3 Cl CF3 Br CH2CH3 590 H F CF3 Br CH2CH3 591 Br F CF3 BrCH2CH3 592 Cl F CF3 Br CH2CH3 593 F F CF3 Br CH2CH3 594 CF3 F CF3 BrCH2CH3 595 Br H H Cl CH2CH3 596 Cl H H Cl CH2CH3 597 F H H Cl CH2CH3 598CF3 H H Cl CH2CH3 599 H Br H Cl CH2CH3 600 Br Br H Cl CH2CH3 601 Cl Br HCl CH2CH3 602 F Br H Cl CH2CH3 603 CF3 Br H Cl CH2CH3 604 H Cl H ClCH2CH3 605 Br Cl H Cl CH2CH3 606 Cl Cl H Cl CH2CH3 607 F Cl H Cl CH2CH3608 CF3 Cl H Cl CH2CH3 609 H F H Cl CH2CH3 610 Br F H Cl CH2CH3 611 Cl FH Cl CH2CH3 612 F F H Cl CH2CH3 613 CF3 F H Cl CH2CH3 614 H H Br ClCH2CH3 615 Br H Br Cl CH2CH3 616 Cl H Br Cl CH2CH3 617 F H Br Cl CH2CH3618 CF3 H Br Cl CH2CH3 619 H Br Br Cl CH2CH3 620 Br Br Br Cl CH2CH3 621Cl Br Br Cl CH2CH3 622 F Br Br Cl CH2CH3 623 CF3 Br Br Cl CH2CH3 624 HCl Br Cl CH2CH3 625 Br Cl Br Cl CH2CH3 626 Cl Cl Br Cl CH2CH3 627 F ClBr Cl CH2CH3 628 CF3 Cl Br Cl CH2CH3 629 H F Br Cl CH2CH3 630 Br F Br ClCH2CH3 631 Cl F Br Cl CH2CH3 632 F F Br Cl CH2CH3 633 CF3 F Br Cl CH2CH3634 H H Cl Cl CH2CH3 635 Br H Cl Cl CH2CH3 636 Cl H Cl Cl CH2CH3 637 F HCl Cl CH2CH3 638 CF3 H Cl Cl CH2CH3 639 H Br Cl Cl CH2CH3 640 Br Br ClCl CH2CH3 641 Cl Br Cl Cl CH2CH3 642 F Br Cl Cl CH2CH3 643 CF3 Br Cl ClCH2CH3 644 H Cl Cl Cl CH2CH3 645 Br Cl Cl Cl CH2CH3 646 Cl Cl Cl ClCH2CH3 647 F Cl Cl Cl CH2CH3 648 CF3 Cl Cl Cl CH2CH3 649 H F Cl ClCH2CH3 650 Br F Cl Cl CH2CH3 651 Cl F Cl Cl CH2CH3 652 F F Cl Cl CH2CH3653 CF3 F Cl Cl CH2CH3 654 H H F Cl CH2CH3 655 Br H F Cl CH2CH3 656 Cl HF Cl CH2CH3 657 F H F Cl CH2CH3 658 CF3 H F Cl CH2CH3 659 H Br F ClCH2CH3 660 Br Br F Cl CH2CH3 661 Cl Br F Cl CH2CH3 662 F Br F Cl CH2CH3663 CF3 Br F Cl CH2CH3 664 H Cl F Cl CH2CH3 665 Br Cl F Cl CH2CH3 666 ClCl F Cl CH2CH3 667 F Cl F Cl CH2CH3 668 CF3 Cl F Cl CH2CH3 669 H F F ClCH2CH3 670 Br F F Cl CH2CH3 671 Cl F F Cl CH2CH3 672 F F F Cl CH2CH3 673CF3 F F Cl CH2CH3 674 H H CF3 Cl CH2CH3 675 Br H CF3 Cl CH2CH3 676 Cl HCF3 Cl CH2CH3 677 F H CF3 Cl CH2CH3 678 CF3 H CF3 Cl CH2CH3 679 H Br CF3Cl CH2CH3 680 Br Br CF3 Cl CH2CH3 681 Cl Br CF3 Cl CH2CH3 682 F Br CF3Cl CH2CH3 683 CF3 Br CF3 Cl CH2CH3 684 H Cl CF3 Cl CH2CH3 685 Br Cl CF3Cl CH2CH3 686 Cl Cl CF3 Cl CH2CH3 687 F Cl CF3 Cl CH2CH3 688 CF3 Cl CF3Cl CH2CH3 689 H F CF3 Cl CH2CH3 690 Br F CF3 Cl CH2CH3 691 Cl F CF3 ClCH2CH3 692 F F CF3 Cl CH2CH3 693 CF3 F CF3 Cl CH2CH3 694 Br H H CF3CH2CH3 695 Cl H H CF3 CH2CH3 696 F H H CF3 CH2CH3 697 CF3 H H CF3 CH2CH3698 H Br H CF3 CH2CH3 699 Br Br H CF3 CH2CH3 700 Cl Br H CF3 CH2CH3 701F Br H CF3 CH2CH3 702 CF3 Br H CF3 CH2CH3 703 H Cl H CF3 CH2CH3 704 BrCl H CF3 CH2CH3 705 Cl Cl H CF3 CH2CH3 706 F Cl H CF3 CH2CH3 707 CF3 ClH CF3 CH2CH3 708 H F H CF3 CH2CH3 709 Br F H CF3 CH2CH3 710 Cl F H CF3CH2CH3 711 F F H CF3 CH2CH3 712 CF3 F H CF3 CH2CH3 713 H H Br CF3 CH2CH3714 Br H Br CF3 CH2CH3 715 Cl H Br CF3 CH2CH3 716 F H Br CF3 CH2CH3 717CF3 H Br CF3 CH2CH3 718 H Br Br CF3 CH2CH3 719 Br Br Br CF3 CH2CH3 720Cl Br Br CF3 CH2CH3 721 F Br Br CF3 CH2CH3 722 CF3 Br Br CF3 CH2CH3 723H Cl Br CF3 CH2CH3 724 Br Cl Br CF3 CH2CH3 725 Cl Cl Br CF3 CH2CH3 726 FCl Br CF3 CH2CH3 727 CF3 Cl Br CF3 CH2CH3 728 H F Br CF3 CH2CH3 729 Br FBr CF3 CH2CH3 730 Cl F Br CF3 CH2CH3 731 F F Br CF3 CH2CH3 732 CF3 F BrCF3 CH2CH3 733 H H Cl CF3 CH2CH3 734 Br H Cl CF3 CH2CH3 735 Cl H Cl CF3CH2CH3 736 F H Cl CF3 CH2CH3 737 CF3 H Cl CF3 CH2CH3 738 H Br Cl CF3CH2CH3 739 Br Br Cl CF3 CH2CH3 740 Cl Br Cl CF3 CH2CH3 741 F Br Cl CF3CH2CH3 742 CF3 Br Cl CF3 CH2CH3 743 H Cl Cl CF3 CH2CH3 744 Br Cl Cl CF3CH2CH3 745 Cl Cl Cl CF3 CH2CH3 746 F Cl Cl CF3 CH2CH3 747 CF3 Cl Cl CF3CH2CH3 748 H F Cl CF3 CH2CH3 749 Br F Cl CF3 CH2CH3 750 Cl F Cl CF3CH2CH3 751 F F Cl CF3 CH2CH3 752 CF3 F Cl CF3 CH2CH3 753 H H F CF3CH2CH3 754 Br H F CF3 CH2CH3 755 Cl H F CF3 CH2CH3 756 F H F CF3 CH2CH3757 CF3 H F CF3 CH2CH3 758 H Br F CF3 CH2CH3 759 Br Br F CF3 CH2CH3 760Cl Br F CF3 CH2CH3 761 F Br F CF3 CH2CH3 762 CF3 Br F CF3 CH2CH3 763 HCl F CF3 CH2CH3 764 Br Cl F CF3 CH2CH3 765 Cl Cl F CF3 CH2CH3 766 F Cl FCF3 CH2CH3 767 CF3 Cl F CF3 CH2CH3 768 H F F CF3 CH2CH3 769 Br F F CF3CH2CH3 770 Cl F F CF3 CH2CH3 771 F F F CF3 CH2CH3 772 CF3 F F CF3 CH2CH3773 H H CF3 CF3 CH2CH3 774 Br H CF3 CF3 CH2CH3 775 Cl H CF3 CF3 CH2CH3776 F H CF3 CF3 CH2CH3 777 CF3 H CF3 CF3 CH2CH3 778 H Br CF3 CF3 CH2CH3779 Br Br CF3 CF3 CH2CH3 780 Cl Br CF3 CF3 CH2CH3 781 F Br CF3 CF3CH2CH3 782 CF3 Br CF3 CF3 CH2CH3 783 H Cl CF3 CF3 CH2CH3 784 Br Cl CF3CF3 CH2CH3 785 Cl Cl CF3 CF3 CH2CH3 786 F Cl CF3 CF3 CH2CH3 787 CF3 ClCF3 CF3 CH2CH3 788 H F CF3 CF3 CH2CH3 789 Br F CF3 CF3 CH2CH3 790 Cl FCF3 CF3 CH2CH3 791 F F CF3 CF3 CH2CH3 792 CF3 F CF3 CF3 CH2CH3

In an all reactions the pressure is preferably atmospheric pressureunless stated otherwise.

Where a temperature is stated as from X to Y, X and Y are included inthe temperature range.

The reactions conditions described above are also applicable when thecompounds of formula (I), (III), (IV), (V) and (VI) are compounds offormula (I*), (III*), (IV*), (V*) and (VI*).

The invention will now be described by way of non-limiting Examples.

EXAMPLES Example 1 Preparation of (R)-4-amino-2-ethylisoxazolidin-3-one

To a solution of N-ethyl(hydroxy)ammonium oxalate (5.5 g, 25.7 mmol) ina mixture of ethanol (70 ml) and water (14 ml), was added dropwisetriethylamine (9.8 ml, 70.2 mmol) at ambient temperature and thesolution was stirred for 15 min. To this solution(S)-4-(chloromethyl)oxazolidine-2,5-dione (7.0 g, 46.8 mmol) was addedin several portions. The resulting reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was evaporated under reducedpressure to afford a residue which was purified by trituration with DCM(300 ml) to afford (R)-4-amino-2-ethylisoxazolidin-3-one (3.6 g) as awhite solid. ¹H NMR (400 MHz, CD₃OD) δ 4.6 (t, 1H), 4.2-3.9 (m, 2H),3.7-3.5 (m, 2H), 1.2 (t, 3H).

Example 2 Preparation of (R)-4-amino-2-ethylisoxazolidin-3-one

To a solution of N-ethyl(hydroxy)ammonium oxalate (0.42 g, 1.8 mmol) andtriethylamine (0.7 ml, 5.0 mmol) in chloroform (3 ml) was added(S)-4-(chloromethyl)oxazolidine-2,5-dione (0.50 g, 3.34 mmol) slowly (inseveral portions) at room temperature. The resulting reaction mixturewas stirred at room temperature for 1 h and then at 50° C. for 1.5 h.The reaction mixture was evaporated under reduced pressure and thedesired product was isolated by trituration with DCM to afford(R)-4-amino-2-ethylisoxazolidin-3-one (196 mg) as a white solid. ¹H NMR(400 MHz, CD₃OD) δ 4.6 (t, 1H), 4.2-3.9 (m, 2H), 3.7-3.5 (m, 2H), 1.2(t, 3H).

Example 34-acetyl-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl)]-2-methyl-benzamide

To a suspension of 4-acetyl-2-methyl-benzoic acid (5.0 g, 28 mmol) indichloromethane (20 ml) was added dimethylformamide (0.2 ml) followed bya dropwise addition of oxalyl chloride (4.6 g, 36.48 mmol). The reactionmixture was stirred at ambient temperature until the end of gasevolution (ca. 4 h). The solvent was evaporated under reduced pressureto afford crude 4-acetyl-2-methyl-benzoyl chloride and it was dilutedwith acetonitrile (20 ml). The above prepared solution was addeddropwise to a solution of (R)-4-amino-2-ethylisoxazolidin-3-one (4.6 g,36 mmol) and potassium carbonate (15.0 g, 110 mmol) in acetonitrile (80ml) at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred for further 2 h before being evaporated underreduced pressure. Additional water was added and the aqueous phase wasextracted with DCM (3×50 ml). The organic phase was evaporated underreduced pressure. The crude product was purified by silica gelchromatography (0-40% ethyl acetate in hexane) to afford4-acetyl-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl)]-2-methyl-benzamide(4.3 g) as a pale yellow solid. Chiral HPLC analysis (Chiralpack IA,acetonitrile:THF:water=58:2:40, 0.8 1 ml/min, retention time 5.29minutes (major enantiomer 98.3%) and 4.67 minutes (minor enantiomer1.7%) ¹H NMR (400 MHz, CDCl₃) δ 7.8 (s, 1H), 7.76 (d, 1H), 7.54 (d, 1H),6.54 (brs, 1H), 4.97 (t, 1H), 4.90-4.80 (m, 1H), 4.10-4.00 (m, 1H),3.80-3.60 (m, 2H), 2.60 (s, 3H), 2.5 (s, 3H), 1.25 (t, 3H). LC-MS(methanol, ESI): m/z=291 (M+H, RT=1.33).

Example 4 Preparation of tert-butylN-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (One Pot, Step a and1-3)

A solution of N-ethyl(hydroxy)ammonium oxalate (0.16 g, 0.74 mmol) inthe mixture of ethanol (2 ml) and water (0.5 ml) was treated withN,N-diisopropylethylamine (0.26 g, 2 mmol) at room temperature for 10min. (S)-4-(chloromethyl)oxazolidine-2,5-dione (0.2 g, 1.34 mmol) inethanol (3 ml) was added at 0° C. in one portion. The resulting reactionmixture was stirred at room temperature for 12 h. The reaction mixturewas evaporated under reduced pressure to afford crude4-amino-2-ethylisoxazolidin-3-one as pale yellow gummy mass, dilutedwith water (5 ml) and THF (10 ml). Triethylamine (0.18 ml, 1.34 mmol)and di-tert-butyl dicarbonate (0.3 g, 1.34 mmol) were added at 0° C.sequentially. The reaction mixture was allowed to warm to roomtemperature and stirred for further 5 h before being evaporated underreduced pressure. Water (10 ml) was added and the aqueous phase wasextracted with DCM (2×25 ml). The combined organic phases were driedover anhydrous Na₂SO₄ and evaporated under reduced pressure. The crudeproduct was purified by silica gel chromatography (0-10% EtOAc incyclohexane) to afforded tert-butylN-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.16 g) as acolorless liquid. Chiral HPLC analysis (Chiralpack IA,acetonitrile:THF:water=58:2:40, 0.8 1 ml/min, retention time 5.43minutes (major 96.6%) and 4.89 minutes (minor 2.8%).

¹H NMR (400 MHz, CDCl₃) δ 5.11 (brs, 1H), 4.78-4.67 (m, 1H), 4.59-4.47(m, 1H), 3.95 (dd, 1H), 3.72-3.54 (m, 2H), 1.45 (s, 9H), 1.23 (t, 3H)

Example 5 Preparation of(2S)-2-amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamidehydrochloride

Acetic acid (2 ml) was added to a mixture of(S)-4-(chloromethyl)oxazolidine-2,5-dione (0.50 g, 3.34 mmol) andN-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride (0.56 g, 3.68 mmol).The reaction mixture was stirred at room temperature for 12 h andevaporated under reduced pressure to afford 985 mg of the title compound(75% Quantitative NMR mass purity) as white solid.

¹H NMR (400 MHz, CD₃OD) δ=4.88-4.85 (m, 1H), 4.51-4.48 (m, 2H),4.21-4.09 (m, 2H) ppm.

¹⁹F NMR (400 MHz, DMSO) δ=−71.5 ppm.

Example 6 Preparation of(4R)-4-amino-2-(2,2,2-trifluoroethyl)isoxazolidin-3-one

(2S)-2-amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamidehydrochloride (0.10 g, 0.27 mmol, 75 mass % purity), potassium carbonate(0.11 g, 0.80 mmol) and acetonitrile (1 ml) was stirred at 0° C. for 1 hand at room temperature for 12 h. The reaction mixture was filtered andevaporated evaporated under reduced pressure giving 25 mg of the titlecompound (60% Quantitative NMR mass purity) as a white solid.

¹H NMR (400 MHz, CD₃CN) δ 4.48 (t, 1H), 4.23-4.05 (m, 2H), 3.92-3.81 (m,2H).

¹⁹F NMR (400 MHz, DMSO) δ=−69.2 ppm.

Example 74-acetyl-2-methyl-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isoxazolidin-4-yl]benzamide

(2S)-2-amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamidehydrochloride (150 mg, 0.43 mmol, 75 mass % purity), potassium carbonate(0.28 g, 2.0 mmol) and acetonitrile (2 ml) was stirred at 0° C. for 1 h.A solution of 4-acetyl-2-methyl-benzoyl chloride (138 mg, 0.70 mmol) inacetonitrile (2 ml) was added dropwise at 0° C., and then the reactionmixture was allowed to warm up to room temperature and stirred at thistemperature for 1 h. The reaction mixture was filtered and evaporatedunder reduced pressure. The crude product was purified by silica gelchromatography (0-100% ethyl acetate in hexane) to afford4-acetyl-2-methyl-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isoxazolidin-4-yl]benzamide(107 mg) as a white solid. Chiral HPLC analysis (Chiralpack IA,hexane:2-propanol=90:10, 1 ml/min, retention time 13.2 minutes (major98%) and 15.1 minutes (minor 2%).

¹HNMR (CDCl₃): δ 7.82 (s, 1H), 7.79 (d, 1H, 8 Hz), 7.52 (d, 1H, 8 Hz),6.46 (bs, 1H), 5.06-4.93 (m, 1H), 4.31-4.06 (m, 2H), 2.52 (s, 3H) ppm.

¹⁹F NMR (CDCl₃): δ−70.28 ppm

Example 8 Preparation of(4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide

To a suspension of (4R)-2-oxooxazolidine-4-carboxylic acid (0.500 g,3.81 mmol) in 1,2-dichloroethane (5 ml) was added 3 dropsdimethylformamide followed by a dropwise addition of oxalyl chloride(0.543 g, 4.20 mmol). The reaction mixture was stirred at ambienttemperature until the end of gas evolution (ca. 1 h). The above preparedsolution was added dropwise to a solution of N-ethyl(hydroxy)ammoniumoxalate (0.874 g, 4.12 mmol) and triethylamine (1.38 g, 13.5 mmol) in1,2-dichloroethane (5 ml) at 0° C. The reaction mixture was allowed towarm to room temperature and stirred for further 2 h before beingevaporated under reduced pressure. Tetrahydrofuran (20 ml) was added tothe residue and the mixture was heated to 40 C for 15 min. Theprecipitate was filtered off and the filtrate was evaporated underreduced pressure. The crude product was purified by silica gelchromatography (0-5% MeOH in DCM) to afford(4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.409 g) as alight yellow solid. Chiral HPLC analysis (Chiralpack IC,Ethanol:2-propanol=05:95, 1 ml/min, retention time 4.54 minutes (onlyenantiomer)).

¹H NMR (400 MHz, CD₃OD) δ 4.84 (m, 1H), 4.67 (t, 1H), 4.33 (dd, 1H),3.64 (dq, 2H), 1.19 (t, 3H)

Example 9 Preparation of (4R)-4-amino-2-ethyl-isoxazolidin-3-one

To a solution of (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide(0.030 g, 0.172 mmol) in THF (0.4 ml) and water (0.13 ml) was addedtriethylamine (0.035 g, 0.34 mmol) and the resulting reaction mixturewas stirred at room temperature for 16 h. Additional water was added andthe aqueous phase was extracted with DCM (3×). The aqueous phase wasevaporated under reduced pressure to afford(4R)-4-amino-2-ethyl-isoxazolidin-3-one (0.0175 g) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 4.6 (t, 1H), 4.2-3.9 (m, 2H), 3.7-3.5 (m, 2H),1.2 (t, 3H).

Example 10 Preparation of tert-butylN-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate

To a solution of (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide(0.100 g, 0.574 mmol) in THF (1.2 ml) and water (0.4 ml) was addedtriethylamine (0.117 g, 1.15 mmol) and the resulting reaction mixturewas stirred at room temperature for 16 h. Di-tert-butyl dicarbonate(0.136 g, 0.603 mmol) was added and the reaction mixture was stirred fora further 1 h. Additional water was added and the aqueous phase wasextracted with ethyl acetate (3×). The combined organic phases weredried over anhydrous Na₂SO₄ and evaporated under reduced pressure. Thecrude product was purified by silica gel chromatography (0-70% EtOAc incyclohexane) to afford tert-butylN-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.0850 g) as a whitecrystalline solid. Chiral HPLC analysis (Chiralpack IC,heptane:ethanol=80:20, 1 ml/min, retention time 2.85 minutes (minorenantiomer 0.4%) and 4.73 minutes (major enantiomer 99.6%)). ¹H NMR (400MHz, CDCl₃) δ 5.11 (brs, 1H), 4.78-4.67 (m, 1H), 4.59-4.47 (m, 1H), 3.95(dd, 1H), 3.72-3.54 (m, 2H), 1.45 (s, 9H), 1.23 (t, 3H)

Alternatively, the title compound can be obtained by carrying out thefollowing procedure:

To a solution of (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide(0.100 g, 0.574 mmol) in THF (1.2 ml) and water (0.4 ml) was added K₂CO₃(0.0794 g, 0.574 mmol) and the resulting reaction mixture was stirred atroom temperature for 16 h. Di-tert-butyl dicarbonate (0.136 g, 0.603mmol) was added and the reaction mixture was stirred for a further 1 h.Additional water was added and the aqueous phase was extracted withethyl acetate (3×). The combined organic phases were dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The crudeproduct was purified by silica gel chromatography (0-70% EtOAc incyclohexane) to afford tert-butylN-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.070 g) as a whitecrystalline solid. Chiral HPLC analysis (Chiralpack IC,heptane:ethanol=80:20, 1 ml/min, retention time 2.85 minutes (minorenantiomer 0.4%) and 4.73 minutes (major enantiomer 99.6%)).

Example 11 Preparation of(4R)-N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide

To a suspension of (4R)-2-oxooxazolidine-4-carboxylic acid (0.150 g,1.14 mmol) in dry THF (1.5 ml) was added a drop of dimethylformamidefollowed by a dropwise addition of oxalyl chloride (0.11 ml, 1.25 mmol).The reaction mixture was stirred at ambient temperature for 20 minutes.The above prepared solution was added dropwise to a suspension ofN-phenylhydroxylamine (0.158 g, 1.37 mmol) and Na₂CO₃ (0.182 g, 1.72mmol) in THF (1.5 ml) at 0° C. The resulting reaction mixture wasstirred at ambient temperature for 1.5 h. The precipitate was filteredoff and to the filtrate was added aqueous saturated NaHCO₃ and ethylacetate. The phases were separated and the aqueous phase was extractedwith EtOAc (3×). The combined organic phases were dried over anhydrousMgSO₄ and evaporated under reduced pressure. The crude product waspurified by silica gel chromatography (0-5% MeOH in DCM) to afford(4R)-N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide (0.1802 g) as abeige solid.

¹H NMR (400 MHz, CD₃OD) δ 7.71-7.61 (m, 2H), 7.45-7.34 (m, 2H),7.26-7.18 (m, 1H), 5.04 (dd, J=9.2, 5.0 Hz, 1H), 4.78 (t, J=9.2 Hz),4.50 (dd, J=8.8, 5.0 Hz, 1H).

Example 12 Preparation of tert-butylN-[(4R)-3-oxo-2-phenyl-isoxazolidin-4-yl]carbamate

To a solution of (4R)-N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide(0.100 g, 0.450 mmol) in THF (1.0 ml) and water (0.3 ml) was addedtriethylamine (0.127 ml, 0.900 mmol). The resulting solution was stirredin a closed vial at 70° C. for 2.5 h. The reaction mixture was cooled toambient temperature and di-tertbutyldicarbonate (0.111 g, 0.495 mmol)was added. The reaction mixture was stirred for another 1.5 h, dilutedwith water and extracted with EtOAc (3×). The combined organic phaseswere dried over anhydrous MgSO₄ and evaporated under reduced pressure.The crude product was purified by silica gel chromatography (0-23% EtOAcin cyclohexane) to afford tert-butylN-[(4R)-3-oxo-2-phenyl-isoxazolidin-4-yl]carbamate (0.0902 g) as a beigesolid.

¹H NMR (400 MHz, CDCl₃) δ 7.73-7.67 (m, 2H), 7.43-7.36 (m, 2H),7.22-7.16 (m, 1H), 5.23 (br, 1H), 5.00-4.89 (m, 1H), 4.85-4.74 (m, 1H),4.19 (dd, J=8.5, 11.0 Hz, 1H), 1.48 (s, 9H).

Example 13 Preparation ofN-hydroxy-N-methyl-2-oxo-oxazolidine-4-carboxamide

To a suspension of 2-oxooxazolidine-4-carboxylic acid (0.200 g, 1.53mmol) in dry 1,2-dichloroethane (2.0 ml) was added a drop ofdimethylformamide followed by a dropwise addition of oxalyl chloride(0.144 ml, 1.68 mmol). The reaction mixture was stirred at ambienttemperature for 30 minutes. The above prepared solution was addeddropwise to a suspension prepared by mixing triethylamine (0.52 ml, 3.66mmol) and N-methylhydroxylamine hydrochloride (0.143 g, 1.68 mmol) in1,2-dichloroethane (2.0 ml). The resulting brownish reaction mixture wasstirred at ambient temperature for 1 h. The reaction mixture wasevaporated under reduced pressure and the residue was suspended in THF(8.0 ml). This suspension was heated at 50° C. for 10 min and theremaining brown precipitate was filtered off. The filtrate wasevaporated under reduced pressure to provide the crude product as asticky yellow oil. Purification by silica gel chromatography (0-10% MeOHin DCM) afforded N-hydroxy-N-methyl-2-oxo-oxazolidine-4-carboxamide(0.120 g) as a colorless oil which solidified upon standing.

¹H NMR (400 MHz, CD₃OD) δ 4.87 (dd, J=9.5, 5.1 Hz, 1H), 4.67 (t, J=9.4Hz, 1H), 4.36 (dd, J=9.0, 5.3 Hz, 1H), 3.23 (s, 3H).

Example 14 Preparation of tert-butylN-(2-methyl-3-oxo-isoxazolidin-4-yl)carbamate

To a solution of N-hydroxy-N-methyl-2-oxo-oxazolidine-4-carboxamide(0.120 g, 0.749 mmol) in a mixture of THF (1.5 ml) and water (0.50 ml)was added triethylamine (0.21 ml, 1.50 mmol) and the resulting solutionwas stirred at ambient temperature for 18 h. Di-tertbutyldicarbonate(0.173 g, 0.787 mmol) was added and the reaction mixture was stirred foranother 2 h. The reaction mixture was diluted with DCM and water,aqueous phase was extracted with DCM (3×) and the combined organiclayers were dried over anhydrous MgSO₄ and evaporated under reducedpressure. The crude product was purified by silica gel chromatography(0-50% EtOAc in cyclohexane) to afford tert-butylN-(2-methyl-3-oxo-isoxazolidin-4-yl)carbamate (0.0546 g) as a whitepowder.

¹H NMR (400 MHz, CDCl₃) δ 5.32 (br, 1H), 4.71-4.60 (m, 1H), 4.58-4.44(m, 1H), 3.96 (dd, J=10.3, 8.4 Hz, 1H), 3.17 (s, 3H), 1.41 (s, 9H).

Example 15 Preparation of(4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide

To a suspension of (4R)-2-oxooxazolidine-4-carboxylic acid (10.0 g, 75.9mmol) in dry THF (50 ml) was added three drops of DMF followed by adropwise addition of oxalyl chloride (7.31 ml, 83.5 mmol) at 0° C. Afterthe addition the reaction mixture was stirred for another 30 min atambient temperature. In a separate flask triethylamine (37.2 ml, 266mmol) was slowly added to a solution of N-ethylhydroxylaminehydrochloride in THF (100 ml). To this formed thick white suspension wasadded a solution of acid chloride prepared above over 45 min at 0 C.After finishing of addition the reaction mixture was warmed up toambient temperature, additional THF (50 ml) was added and the reactionmixture was brought to reflux. The remaining precipitate (triethylaminehydrochloride) was filtered off and the filtrate was concentrated underreduced pressure to afford crude product (15.9 g). Quantitative NMRanalysis using trimethoxy benzene as an internal standard indicated thatthe mixture contains(4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (11.39 g) as themajor component. Crystallization of the crude product from methanolafforded (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (8.86 g)as a white powder.

¹H NMR (400 MHz, D₂O) δ 5.01 (dd, J=9.9, 5.9 Hz), 4.77 (t, J=9.2 Hz,1H), 4.39 (dd, J=9.0, 5.7 Hz, 1H), 3.65 (q, J=7.1 Hz, 2H), 1.16 (t,J=7.1 Hz, 3H).

Example 16 Preparation of (4R)-4-amino-2-ethyl-isoxazolidin-3-onehydrochloride

To a suspension of(4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (13.09 g, 74.8mmol) in water (35 ml) was added triethylamine (1.05 ml, 7.48 mmol) andthe resulting mixture was heated at 70° C. for 2 h (clear solution atthis temperature). The reaction mixture was cooled to ambienttemperature and 37% aq HCl (7.5 ml, 89.7 mmol) was slowly added. Theresulting mixture was evaporated under reduced pressure and the residuedried under vacuum to afford (4R)-4-amino-2-ethyl-isoxazolidin-3-onehydrochloride (13.6 g) as a white powder mixed with 10% of triethylaminehydrochloride. Stereochemical integrity was checked by converting asmall portion of the product to tert-butylN-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (see example 10) bytreating hydrochloride salt with triethylamine (1.1 eq) anddi-tertbutyldicarbonate (1.2 eq) in THF. Chiral HPLC analysis(Chiralpack IA, heptane:ethanol=80:20, 1 ml/min, retention time 2.82minutes (minor enantiomer 0%) and 4.10 minutes (major enantiomer 100%))¹H NMR (400 MHz, D₂O) δ 4.58 (t, J=8.1 Hz, 1H), 4.10-4.04 (m, 1H),4.02-3.96 (m, 1H), 3.68-3.51 (m, 2H), 1.18 (t, J=7.0 Hz, 3H).

Alternatively, the title compound can be obtained by carrying out thefollowing procedure:

At 0-5° C., a suspension of sodium (4R)-2-oxooxazolidine-4-carboxylate(10.06 g, 85.1% purity, 55.9 mmol) and Aliquat® 336 (0.56 g, 1.39 mmol)in 2-methyl-tetrahydrofurane (70 ml) was successively treated withN,N-dimethylformamide (0.21 g, 2.87 mmol) and oxalyl chloride (8.58 g,67.6 mmol). The reaction mixture was stirred for 90 min at ambienttemperature and added dropwise to a suspension of triethylamine (13.1 g,0.129 mol) and N-ethylhydroxylamine hydrochloride (4.99 g, 89.9% purity,0.046 mol) in 2-methyl-tetrahydrofurane (40 ml) at −5° C. The resultingbrownish mixture was stirred for 30 min at ambient temperature andwashed with water (2×75 ml). The combined aqueous layers containing theintermediate (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide wereheated to 45° C., treated with aq. NaOH (30% (w/w) soln., 2.95 g, 22.1mmol), and stirred for additional 60 min. A part of water (35 g) wasremoved by distillation and the mixture was treated with aq. HCl (32%(w/w), 9.3 g, 81.6 mmol) to reach pH 1. The distillation was continuedto finally obtain crude (4R)-4-amino-2-ethyl-isoxazolidin-3-onehydrochloride (56 g, ca. 9% solution in water as analyzed byquantitative ¹H-NMR analysis).

Alternatively, the title compound can be obtained by carrying out thefollowing procedure:

A suspension of sodium (4R)-2-oxooxazolidine-4-carboxylate (10.0 g,95.0% purity, 62.1 mmol) and Aliquat® 336 (0.66 g, 1.63 mmol) in ethylacetate (80 ml) was successively treated with HCl in dioxane (4 M soln.,3.1 ml, 12.4 mmol) and N,N-dimethylformamide (0.23 g, 3.15 mmol). Theresulting mixture was treated with a solution of thionyl chloride (9.0g, 75.6 mmol) in ethyl acetate (10 ml) at 10-15° C. within 70 min,stirred at ambient temperature for additional 2 h and added dropwise toa suspension of triethylamine (15.4 g, 0.152 mol) andN-ethylhydroxylamine hydrochloride (6.4 g, 77.0% purity, 50.5 mol) inethyl acetate (65 ml) at 0-5° C. The resulting brownish mixture wasstirred at ambient temperature for 60 min and washed with water (2×50ml). The combined aqueous layers containing the intermediate(4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide were heated to40° C., treated with aq. NaOH (30% (w/w) soln., 13.6 g, 0.102 mol), andstirred for additional 60 min. Apart of water (25 g) was removed bydistillation and the mixture was treated with aq. HCl (32% (w/w) soln.,12.2 g, 0.107 mol) to reach pH 1. The mixture was completely evaporatedto obtain crude (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride(27.1 g, ca. 11.8% purity as determined by quantitative ¹H NMR analysis)as orange solid.

Example 17 Preparation of(4R)-N-benzyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide

To a solution of (4R)-2-oxooxazolidine-4-carboxylic acid (0.300 g, 2.29mmol) in dry tetrahydrofuran (3.0 ml) was added 2 drops of DMF followedby oxalyl chloride (0.22 ml, 2.52 mmol) at 0° C. After stirring at rtfor 20 min the resulting solution was slowly added at 0° C. to asuspension of sodium carbonate (0.603 g, 7.1 mmol) andN-benzylhydroxylamine hydrochloride (0.438 g, 2.75 mmol) intetrahydrofuran (6.0 ml). The reaction mixture was stirred at rt for 2h. The remaining precipitate was filtered off and aq sat. NaHCO₃ wasadded to the filtrate. The aqueous phase was extracted with EtOAc (3×)and combined organic layers were dried over MgSO4 and evaporated underreduced pressure. The crude product was purified by silica gelchromatography (0-5% MeOH in dichloromethane) to afford(4R)-N-benzyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.393 g) as awhite powder.

¹H NMR (400 MHz, CD₃OD) δ 7.38-7.27 (m, 5H), 4.88 (dd, J=9.7, 5.3 Hz,1H), 4.77 (s, 2H), 4.65 (t, J=9.4 Hz, 1H), 4.32 (dd, J=9.0, 5.3 Hz, 1H),3.35 (s, 1H).

Example 18 Preparation of tert-butylN-[(4R)-2-benzyl-3-oxo-isoxazolidin-4-yl]carbamate

To a solution of (4R)-N-benzyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide(0.200 g, 0.847 mmol) in a mixture of THF (1.0 ml) and water (2.0 ml)was added triethylamine (0.24 ml, 1.69 mmol). The resulting reactionmixture was heated in a sealed vial at 70° C. for 3 h. The reactionmixture was diluted with water and extracted with dichloromethane (3×).The combined organic layers were dried over MgSO4 and evaporated underreduced pressure. The crude residue was purified by silica gelchromatography (0-40% EtOAc in CyH) to afford tert-butylN-[(4R)-2-benzyl-3-oxo-isoxazolidin-4-yl]carbamate (0.136 g) as acolorless oil which solidified upon standing.

¹H NMR (400 MHz, CD₃OD) δ 7.39-7.29 (m, 5H), 5.16 (br, 1H), 4.78 (d,J=15.4 Hz, 1H), 4.75-4.68 (m, 1H), 4.68 (d, J=15.8 Hz, 1H), 4.64-4.55(m, 1H), 3.94 (dd, J=10.6, 8.4 Hz, 1H), 1.46 (s, 9H).

Example 19 Preparation of sodium (4R)-2-oxooxazolidine-4-carboxylate

(2R)-2-(Ethoxycarbonylamino)-3-hydroxy-propanoic acid (80 g, 0.452 mol)was dissolved in ethanol (800 ml) at 35° C. and treated in severalportions with sodium hydroxide (24.0 g, 0.600 mol, microprills) at 25°C. After complete addition, the reaction mixture was warmed to 40° C.and stirred overnight. The precipitated solid was filtered off, washedwith ethanol, and dried under reduced pressure to give sodium(4R)-2-oxooxazolidine-4-carboxylate (50.7 g) as a white powdercontaining ca. 20% of the residual solvent.

¹H NMR (400 MHz, D₂O) δ 4.57-4.63 (m, 1H), 4.25-4.31 (m, 2H).

¹H NMR (400 MHz, D₂O/DMSO-d6 4:1) δ 4.63 (dd, J=9.6, 8.5 Hz, 1H), 4.33(dd, J=8.5, 5.8 Hz, 1H), 4.27 (dd, J=9.6, 5.7 Hz, 1H).

Alternatively, the title compound can be obtained by carrying out thefollowing procedure:

At 21° C., a solution of methyl (4R)-2-oxooxazolidine-4-carboxylate(20.0 g, 91.0% purity, 0.125 mol) in acetonitrile (100 g) was treatedwith sodium hydroxide (microprills) in methanol (16.2% (w/w) soln., 37.0g, 0.150 mol) within 60 min and stirred at the ambient temperature foradditional 30 min. The resulting precipitate was filtered off, washedwith acetonitrile (3×25 g) and dried at 100° C. under vacuum to givesodium (4R)-2-oxooxazolidine-4-carboxylate (20 g, 83.2% purity asdetermined by quantitative ¹H NMR analysis) as slightly yellow solid.

Example 20 Preparation of lithium 2-oxooxazolidine-4-carboxylate

At 0-5° C., a solution of methyl 2-oxooxazolidine-4-carboxylate (1.0 g,6.89 mmol) in 2-methyl-tetrahydrofurane (5 g) was treated with asolution of lithium hydroxide (0.167 g, 6.97 mmol) in methanol (2 ml)within 15 min. After complete addition, more methanol (1 ml) was addedand the reaction mixture was stirred at 0-5° C. for additional 60 min.The resulting precipitate was filtered off and dried under vacuum togive lithium 2-oxooxazolidine-4-carboxylate (610 mg) as a white solidcontaining ca. 3% of the residual solvent.

¹H NMR (400 MHz, D₂O) δ 4.57-4.63 (m, 1H), 4.25-4.31 (m, 2H).

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled) 6.A process for the preparation of a compound of formula (I)

comprising i. reacting a compound of formula (II) or a salt thereof

with a compound of formula (V)

in the presence of a suitable base to produce a compound of formula (VI)

and ii. converting the compound of formula (VI) to a compound of formula(I) by treatment of the compound of formula (VI) with an aqueous basewherein R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, C₃-C₆ cycloalkyl, aryl or arylsubstituted by one to five R¹¹, or aryl-C₁-C₄alkylene oraryl-C₁-C₄alkylene substituted by one to five R¹¹; and each R¹¹ isindependently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy,cyano or halogen; R⁷ is hydroxy or halogen or OM where M is Na, K, Li.7. A compound of formula (V)

wherein R⁷ is is OM where M is Na, K, Li.
 8. A compound of formula (VI)

wherein R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, C₃-C₆ cycloalkyl, aryl or arylsubstituted by one to five R¹¹, or aryl-C₁-C₄alkylene oraryl-C₁-C₄alkylene substituted by one to five R¹¹; each R¹¹ isindependently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy,cyano or halogen; or a salt or N-oxide thereof.
 9. (canceled)
 12. Theprocess according to claim 6, wherein the process further comprisesreacting the compound of formula (I) with a second compound, wherein thesecond compound comprises a carboxylic acid, acid halide, ester orthioester functional group, and the reaction comprises reacting theamine functional group of the compound of formula (I) with thecarboxylic acid, acid halide, ester or thioester functional group of thesecond compound such that the compound of formula (I) is coupled to thesecond compound via an amide functional group, or wherein the secondcompound comprises a dicarbonate group, and the reaction comprisesreacting the amine functional group of the compound of formula (I) withthe dicarbonate group of the second compound, such that the compound offormula (I) is coupled to the second compound via a carbamate functionalgroup.
 13. The process according to claim 12, wherein the secondcompound is a compound of formula (XII)

and the process results in a compound of formula (VIII)

wherein X is a leaving group selected from halogen,C₁-C₈alkylsulfonyloxy, C₁-C₈haloalkylsulfonyloxy, C₁-C₈arylsulfonyloxyor C₁-C₈arylsulfonyloxy substituted by one to five R¹¹, or a phosphonateester, cyano, formyl, acetyl, C(O)CH═C(R³)R⁴, C(O)CH₂C(OH)(R³)R⁴ orgroup A

—B¹—B²—B³— is —C═N—O—, —C═N—CH₂—, —C═CH₂—O— or —N—CH₂—CH₂—; A¹, A², A³and A⁴ are independently of one another C—H, C—R⁵, or nitrogen; R³ isC₁-C₈haloalkyl; R⁴ is aryl or aryl substituted by one to three R⁶, or R⁴is heterocyclyl or heterocyclyl substituted by one to three R⁶; each R⁵is independently halogen, cyano, nitro, C₁-C₈alkyl, C₃-C₈cycloalkyl,C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl,C₂-C₈haloalkynyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy, C₁-C₈alkoxycarbonyl-, ortwo R⁵ on adjacent carbon atoms together form a —CH═CH—CH═CH— bridge ora —N═CH—CH═CH— bridge; each R⁶ is independently halogen, cyano, nitro,C₁-C₈alkyl, C₁-C₈haloalkyl, C₁-C₈alkoxy, or C₁-C₈haloalkoxy; R⁸ ishydroxy, C₁-C₆alkoxy, fluoro, chloro, bromo, or SR^(x) wherein R^(x) isH, C₁-C₆alkyl, imidazole or pyrrole; and each R¹¹ is independentlyC₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, cyano orhalogen; R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted byone to five R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substitutedby one to five R¹¹; and each R¹¹ is independently C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, cyano or halogen; or thesecond compound is a compound of formula (XIII)

wherein and the process results in a compound of formula (IX)

wherein R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted byone to five R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substitutedby one to five R¹¹; and R⁹ is hydrogen, C₁-C₈alkyl or C₁-C₈haloalkyl andR⁹ is as defined for compound of formula (XII); each R¹¹ isindependently C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy,cyano or halogen; or the second compound is a compound of formula (XIVa)or (XIVb)

and the process results in a compound of formula X

wherein R¹ is C₁-C₈alkyl, C₁-C₈haloalkyl, aryl or aryl substituted byone to five R¹¹, or aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene substitutedby one to five R¹¹; each R¹⁹ is independently C₁-C₈alkyl,C₁-C₈haloalkyl, aryl-C₁-C₄alkylene- or aryl-C₁-C₄alkylene-substituted byone to five R¹¹; each R¹¹ is independently C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₄alkoxy, C₁-C₄haloalkoxy, cyano or halogen.
 14. (canceled)